CA1341176C - Macrocylic compounds - Google Patents
Macrocylic compoundsInfo
- Publication number
- CA1341176C CA1341176C CA000543027A CA543027A CA1341176C CA 1341176 C CA1341176 C CA 1341176C CA 000543027 A CA000543027 A CA 000543027A CA 543027 A CA543027 A CA 543027A CA 1341176 C CA1341176 C CA 1341176C
- Authority
- CA
- Canada
- Prior art keywords
- tetraazacyclododecane
- triacetic acid
- acid
- carbon atoms
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 90
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 46
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 28
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 25
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 229910052751 metal Inorganic materials 0.000 claims abstract description 20
- 239000002184 metal Substances 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 18
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- 150000002678 macrocyclic compounds Chemical class 0.000 claims abstract description 13
- 125000002252 acyl group Chemical group 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 210000000056 organ Anatomy 0.000 claims abstract description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229920001059 synthetic polymer Polymers 0.000 claims abstract description 5
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical class C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 3
- -1 C1-4-alkylcarbonyl Chemical group 0.000 claims description 80
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 13
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 13
- 229920002521 macromolecule Polymers 0.000 claims description 13
- 239000007983 Tris buffer Substances 0.000 claims description 8
- 230000002285 radioactive effect Effects 0.000 claims description 7
- 230000006872 improvement Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- DPVODUWBAQYLOD-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-[2-[carboxymethyl-[2-[carboxymethyl-[2-[carboxymethyl-[2-oxo-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]ethyl]amino]ethyl]amino]ethyl]amino]acetyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C(=O)(O)CN(CCN(CC(=O)O)CC(=O)N1CCN(CCN(CCN(CC1)CC(=O)O)CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)N1CCN(CCN(CCN(CC1)CC(=O)O)CC(=O)O)CC(=O)O DPVODUWBAQYLOD-UHFFFAOYSA-N 0.000 claims description 3
- MPGOQNRGWHUTAS-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-10-[2-hydroxy-3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]propyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN1CC(O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 MPGOQNRGWHUTAS-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 230000005298 paramagnetic effect Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- 229940039227 diagnostic agent Drugs 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- ZCOJHMOVIBPXAC-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-[4-oxo-4-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]butanoyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CCN1C(=O)CCC(=O)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 ZCOJHMOVIBPXAC-UHFFFAOYSA-N 0.000 claims 2
- FLYQDQKBWHHBGX-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-10-[3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]propyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCN(CC(O)=O)CCN(CC(=O)O)CCN1CCCN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 FLYQDQKBWHHBGX-UHFFFAOYSA-N 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 229910052692 Dysprosium Inorganic materials 0.000 claims 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims 1
- 239000007791 liquid phase Substances 0.000 claims 1
- 229910052748 manganese Inorganic materials 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 150000003839 salts Chemical class 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 22
- 150000002500 ions Chemical class 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 229940086542 triethylamine Drugs 0.000 description 16
- 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 15
- 229960000443 hydrochloric acid Drugs 0.000 description 15
- 235000011167 hydrochloric acid Nutrition 0.000 description 15
- 239000002872 contrast media Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- BPEUICGMDOXPJJ-UHFFFAOYSA-N ethyl 2-[4,7-bis(2-ethoxy-2-oxoethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1 BPEUICGMDOXPJJ-UHFFFAOYSA-N 0.000 description 13
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000001768 cations Chemical class 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 150000007530 organic bases Chemical class 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 229940039231 contrast media Drugs 0.000 description 10
- 125000000524 functional group Chemical group 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000007529 inorganic bases Chemical class 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 230000000903 blocking effect Effects 0.000 description 7
- 230000001747 exhibiting effect Effects 0.000 description 7
- 150000007522 mineralic acids Chemical class 0.000 description 7
- 150000007524 organic acids Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 229940093915 gynecological organic acid Drugs 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 235000005985 organic acids Nutrition 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000536 complexating effect Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- 239000008139 complexing agent Substances 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229910044991 metal oxide Inorganic materials 0.000 description 4
- 150000004706 metal oxides Chemical class 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 238000003325 tomography Methods 0.000 description 4
- FURLCQRFFWBENR-UHFFFAOYSA-N 1-benzyl-1,4,7,10-tetrazacyclododecane Chemical compound C=1C=CC=CC=1CN1CCNCCNCCNCC1 FURLCQRFFWBENR-UHFFFAOYSA-N 0.000 description 3
- OZWGNPVYVRIYRI-UHFFFAOYSA-N 1-benzyl-4,7,10-tris-(4-methylphenyl)sulfonyl-1,4,7,10-tetrazacyclododecane Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CCN(CC=2C=CC=CC=2)CC1 OZWGNPVYVRIYRI-UHFFFAOYSA-N 0.000 description 3
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- WOMTYMDHLQTCHY-UHFFFAOYSA-N 3-methylamino-1,2-propanediol Chemical compound CNCC(O)CO WOMTYMDHLQTCHY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010001497 Agitation Diseases 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
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- 229920000136 polysorbate Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- HVVNJUAVDAZWCB-UHFFFAOYSA-N prolinol Chemical compound OCC1CCCN1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 238000011363 radioimmunotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000011410 subtraction method Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N thiosemicarbazide group Chemical group NNC(=S)N BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- ORZHVTYKPFFVMG-UHFFFAOYSA-N xylenol orange Chemical compound OC(=O)CN(CC(O)=O)CC1=C(O)C(C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=C(C)C=2)=C1 ORZHVTYKPFFVMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Polyethers (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
1,4,7,10-Tetraazacyclododecanes of general Formula II
(see formula II) wherein:
each R1, independently of each other, is hydrogen or metal ion equivalent of a complexible metal;
R2 is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is (see formula III) or -COOR6, wherein R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon atoms, C6-10-aryl or C6-10-ar-C1-4-alkyl, or R2 or R3 represent a second macrocycle of Formula II', (see formula II') which is of a structure the same as or different from that of the basic skeleton of Formula II, linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or R2 is B or CH2-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor;
are valuable complex-forming compounds and complexes for diagnostics and therapy. They are useful, e.g., in NMR and X-ray diagnostics.
(see formula II) wherein:
each R1, independently of each other, is hydrogen or metal ion equivalent of a complexible metal;
R2 is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is (see formula III) or -COOR6, wherein R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon atoms, C6-10-aryl or C6-10-ar-C1-4-alkyl, or R2 or R3 represent a second macrocycle of Formula II', (see formula II') which is of a structure the same as or different from that of the basic skeleton of Formula II, linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or R2 is B or CH2-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor;
are valuable complex-forming compounds and complexes for diagnostics and therapy. They are useful, e.g., in NMR and X-ray diagnostics.
Description
MACROCYCLIC COMPOUNDS
This invention relates to macrocyclic complexing compounds or agents, complexes of metal ions therewith (i.e., complex salts) and complex salts of said complexes, agents, e.g., pharmaceutical agents, containing these compounds, their use as diagnostics and therapeutics, as well as to processes for the preparation of these compounds and agents.
Consideration has been given to the use of metal complexes as contrast media for radiology as early as the beginning of the fifties. The compounds then utilized, however, showed such high toxicity that administration to human patients could not be considered. Therefore, the realization was definitely 1341 176 ' surprising that certain complex salts proved to have adequate compatibility to be considered for routine use in human patients for diagnostic purposes. As the first representative of this class of compounds, the dimeglumine salt of Gd DTPA [the gadolinium (III) complex of diethylenetriaminepentaacetic acid] described in European Patent Application, Publication No. 71564 (See United States Patent Number 4,647,447), has very well proven itself thus far as a contrast medium for nuclear spin tomography in clinical testing on more than one thousand patients. The compound is primarily used in connection with diseases of the central nervous system.
An important reason for the good compatibility of Gd DTPA in clinical usage resides in high efficacy in nuclear spin tomography, especially for many brain tumors. On account of its high efficacy, Gd DTPA can be administered, e.g., at 0.1 mmol/kg body weight, at a very much lower dose than, for example, X-ray contrast media in many X-ray examinations.
As a further representative of the complex salts, the meglumine salt of Gd DOTA [gadolinium(III) complex of 1,4,7,10-tetraazacyclododecanetetraacetic acid], the subject of United States Patent Number 4,647,447 and Canadian Patent Number 1,256,249 has proved to be well suited for diagnostic purposes.
However, it is desirable to employ chelates even in higher doses. This is the case, in particular for identification of specific diseases outside of the central nervous system with the aid of nuclear spin tomography (NMR diagnostics), but quite especially when using chelates as X-ray contrast media.
Chelates can offer a number of advantages over iodinated X-ray contrast media:
(a) Radiation absorption in the higher energy range;
~~~~~!
This invention relates to macrocyclic complexing compounds or agents, complexes of metal ions therewith (i.e., complex salts) and complex salts of said complexes, agents, e.g., pharmaceutical agents, containing these compounds, their use as diagnostics and therapeutics, as well as to processes for the preparation of these compounds and agents.
Consideration has been given to the use of metal complexes as contrast media for radiology as early as the beginning of the fifties. The compounds then utilized, however, showed such high toxicity that administration to human patients could not be considered. Therefore, the realization was definitely 1341 176 ' surprising that certain complex salts proved to have adequate compatibility to be considered for routine use in human patients for diagnostic purposes. As the first representative of this class of compounds, the dimeglumine salt of Gd DTPA [the gadolinium (III) complex of diethylenetriaminepentaacetic acid] described in European Patent Application, Publication No. 71564 (See United States Patent Number 4,647,447), has very well proven itself thus far as a contrast medium for nuclear spin tomography in clinical testing on more than one thousand patients. The compound is primarily used in connection with diseases of the central nervous system.
An important reason for the good compatibility of Gd DTPA in clinical usage resides in high efficacy in nuclear spin tomography, especially for many brain tumors. On account of its high efficacy, Gd DTPA can be administered, e.g., at 0.1 mmol/kg body weight, at a very much lower dose than, for example, X-ray contrast media in many X-ray examinations.
As a further representative of the complex salts, the meglumine salt of Gd DOTA [gadolinium(III) complex of 1,4,7,10-tetraazacyclododecanetetraacetic acid], the subject of United States Patent Number 4,647,447 and Canadian Patent Number 1,256,249 has proved to be well suited for diagnostic purposes.
However, it is desirable to employ chelates even in higher doses. This is the case, in particular for identification of specific diseases outside of the central nervous system with the aid of nuclear spin tomography (NMR diagnostics), but quite especially when using chelates as X-ray contrast media.
Chelates can offer a number of advantages over iodinated X-ray contrast media:
(a) Radiation absorption in the higher energy range;
~~~~~!
thus reduction of radiation stress on patients and improvement of the prerequisites for the energy subtraction method.
(b) Avoidance of so-called "allergy-like" or cardio-vascular side effects, known as "contrast medium reactions" of the iodinated X-ray contrast agents used nowadays, which effects are unforeseeable, in part even life-threatening or fatal.
The preconditions therefore are:
- high concentration of radiation-absorbing elements in solution (X-ray) or a strong influence on the NMR signals:
- pharmacokinetics suitable for diagnostics:
- a very firm bond of the metal ions in excretable complexes, even under in vivo conditions;
- good compatibility of the highly concentrated, high-dosage complex solution:
- low allergic potential of all components of tire contrast medium: and - high stability and long shelf life of the chemical ingredients of the contrast solution.
These requirements apply to varying degrees and in various ways, but basically hold true for all applications of the aforementioned complexes in in vivo diagnostics as well as, in part, in therapy.
The present invention provides new such complexes, preferably which satisfy the foregoing requirements.
Consistent with the present invention there are provided _--.
(b) Avoidance of so-called "allergy-like" or cardio-vascular side effects, known as "contrast medium reactions" of the iodinated X-ray contrast agents used nowadays, which effects are unforeseeable, in part even life-threatening or fatal.
The preconditions therefore are:
- high concentration of radiation-absorbing elements in solution (X-ray) or a strong influence on the NMR signals:
- pharmacokinetics suitable for diagnostics:
- a very firm bond of the metal ions in excretable complexes, even under in vivo conditions;
- good compatibility of the highly concentrated, high-dosage complex solution:
- low allergic potential of all components of tire contrast medium: and - high stability and long shelf life of the chemical ingredients of the contrast solution.
These requirements apply to varying degrees and in various ways, but basically hold true for all applications of the aforementioned complexes in in vivo diagnostics as well as, in part, in therapy.
The present invention provides new such complexes, preferably which satisfy the foregoing requirements.
Consistent with the present invention there are provided _--.
macrocyclic compounds characterized by general Formula I
U~-~~-(U2-D2) _A1 s (I)~
U _0~_!U3_03)t_A2 wherein Y is a nitrogen or phosphorus atom, Al and A2, being identical or different, each mean a straight-chain or branched alkylene group of 2-6 carbon atoms, U1, U2, U3 and U4, being identical or different, each mean a direct bond or a straight-chain or branched alkylene group of 1-6 carbon atoms, Dl, D2, D3 and D4, being identical or different, respectively mean an oxygen or sulfur atom, an alkylene group of 1-6 carbon atoms, or a group N-R~
wherein R~ means a hydrogen atom, a straight-chain or branched alkylene chain of 1-4 carbon atoms carrying at the end a COOR1 group with R1 being a hydrogen atom or a metal ion equivalent, D5 has one of the meanings given for Dl, D2, D3 and D4 and can also mean i the group -CH- wherein R5 means a hydrogen atom or a straight-chain or branched, saturated or unsaturated Cl-C20-hydrocarbylene, e.g., alkylene group, optionally containing imino, phenylenoxy, phenylenimino, phenylene amide, an ester group and/or oxygen, sulfur and/or nitrogen, and/or optionally substituted by hydroxy, mercapto, epoxy, oxo, thioxm,imino and/or amino group(s), this alkylene group exhibiting at the end either a functional group or, linked via the latter, a macromolecule B, s and t mean integers from 0 to 5, RZ means hydrogen; a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acylalkylene group of 1-16 carbon atoms optionally substituted by one or several hydroxy or lower alkoxy groups; -CH2-X-V wherein X means carbonyl, a straight-chain or branched-chain alkylene group of 0-10 carbon atoms, optionally substituted by one or several hydroxy or lower alkoxy groups; or a straight-chain or branched-chain alkylene group of 5-23 carbon atoms, interrupted by oxygen atoms; but wherein formyl is not 1o substituted by hydroxy; V means N~R3 , or -COOR6 wherein ~Rq R3 and R9, independently of each other, mean hydrogen, a linear or branched alkyl group of 1-16 carbon atoms substituted, if desired, by one or several hydroxy or lower alkoxy groups, or R3 and R4 together with the nitrogen atom mean a five- or six-membered ring which is saturated and optionally contains a further hetero atom, and R6 means a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon residue of up to 16 carbon atoms, or an 2o aryl or aralkyl group, or RZ or R3 mean a second macrocycle of Formula I', U~-0~-(UZ-~215-~~
lI~), which can be of a structure different from the basic skeleton of the first macrocycle, and which is linked by way of an alkylene chain containing 2-20 carbon atoms, 30 optionally carrying carbonyl groups at the ends and being interrupted, if desired, by one or several oxygen atoms or R1-carboxymethylimino groups or being substituted by one or several hydroxy, lower alkoxy or carboxy-lower alkyl groups, or RZ means B or CHZ-COB, with the provisos that, if RZ
stands for B or CHZ-COB, R5 is a hydrogen atom; that at least two COOR1 groups are present in the molecule; and that there are at least two hetero atoms in the macrocycle and that two hetero atoms of the macrocycle are linked to each other by way of an alkylene group with at least two carbon atoms; and 1o wherein functional groups present in the molecule are, if desired, conjugated with macromolecules and, if desired, free carboxy groups are used to form a salt with organic or inorganic bases or amino acids, and/or alkaline groups and are used to form a salt with inorganic or organic acids.
In particular, 1,4,7,10-tetraazacyclododecane derivatives of general Formula II are preferred R ~ 0 0 C--~~N/
(II), R ~ OOC-/N~/N~COOR ~
wherein:
each R1, independently of each other, is hydrogen or a metal ion equivalent of a complexible metal;
RZ is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, or -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is _N--""~R3 or -COOR6, wherein r.~ ~ ~~4 R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon to atoms, C6-io-aryl or C6-io-ar-C1_4-alkyl, or R2 or R3 represent a second macrocycle of Formula II', R ~ 0 0 C--~N~N~
(II~), R~OOC-/N~N~COOR2 which is of a structure the same as or different from that of the basic skeleton of Formula II, 20 linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or RZ is B or CHZ-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor, and functional groups present in the molecule are, if 3o desired, conjugated with biomolecules and optionally free carboxy groups are used to form a salt with organic or inorganic bases or amino acids, and alkaline groups are used to form a salt with organic or inorganic acids.
~' > , ~,:.3 1341 17fi _8_ The compounds of this invention and the solutions prepared therefrom fulfill the cited require-ments in a surprising way. They exhibit a high efficacy that can be adapted, by the choice of suitable metal atoms, to the respective principles of the diagnostic or therapeutic method (X-ray, NMR, ultrasonics, nuclear medicine).
The compounds of this invention are utilized, e.g., 1. For NMR diagnostics in the form of their complexes with the ions of the transition metals of atomic numbers 21-29, 42 and 44.
2. For NMR and X-ray diagnostics in the form of their complexes with the ions of the lanthanide elements of atomic numbers 57-70.
3. For ultrasonic diagnostics, those compounds can be employed which are useful in NMR
diagnostics, as well as those useful in X-ray diagnostics.
4. For radiodiagnostics and radiotherapy in '6 the form of their complexes with the radioisotopes of the elements of atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 62, 64, 70 or 77.
_ Q _ 1341 1 76 J
Even without specific measures, their pharma-cokinetics permit improvement in the diagnosis of numerous diseases. The complexes, for the largest part, are excreted unchanged and quickly so that especially when using relatively toxic metal ions as the active principle, no damaging effects that can be traced back to the metal are observed, in spite of a high dosage.
Practical usage of the novel complexes and complexing agents is also facilitated by their adequate, frequently even .very gobd~ :chemicalwstability.
Another essential advantage of the complexes and complexing agents described resides in their extra-ordinary chemical versatility. Besides by the choice of the central atom, the properties can be adapted by the choice of variegated substituents and/or salt-forming agents to the requirements regarding efficacy, pharmaco-kinetics, compatibility, ability to handle, etc.
Thus, it is possible to attain a specificity of the compounds, very desirable in diagnostics and therapy, for structures in the organism, for certain biochemical substances, for metabolic processes, for conditions prevailing in tissue or body fluids, especially by coupling to biological compounds or to compounds exhibiting interaction with biological systems.
Such compounds suitable for coupling can be of low molecular weight (for example, glucose, amino acids, fatty acids, bile acids, porphyrins) or high-molecular weight (polysaccharides, proteins, antibodies, etc.), or they can also represent structures foreign to the body but exhibiting a specific way of distribution in the body or reacting with components of the body.
. 1341 1 76 - to -Utilization of such principles will be possible the more easily, the more sensitive the detection method for a diagnostic agent, or the more effective a complex, being, for example, labeled radioactively, in therapy.
The compounds of this invention can also be used in radiotherapy in the form of their complexes with radioisotopes, e.g. 192Ir. The complex-forming agents of this invention are furthermore suited, as such or in the form of weak complexes with preferably endogenous ions (Ca2+, Mg2+, Zn2+~ ge2+/3+
for therapy of heavy metal poisoning or storage disea~~rs.
More generally, the compounds can be used in conjunction with any metal ion equivalent as long as the metal is chelatable (complexable) by a complexing agent.of this invention. Thus, the compounds, complexes and complex salts of this invention are also useful for the purposes known in the past for complexes of such metal ions.
Y preferably is N. Suitable alkylene groups throughout the foregoing depending on the number of C-atoms, include, e.g., straight-chained and branched methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, etc.
D's are preferably N-R~.
Compounds of general Formula I wherein R1 is hydrogen are denoted as complexing compounds, and those wherein at least two substituents R1 are metal ion equivalents are called metal complexes.
When R2 is hydrocarbyl, acyl or acylalkylene of 1-16 carbon atoms, this group can be linear or branched, saturated or unsaturated and can optionally be substituted by one or several hydroxy and/or lower alkoxy groups. Suitable lower alkoxy groups contain 1-4 carbon atoms and include, in particular, methoxy and ethoxy groups, but also n- or i-propoxy and n, i, or t-butoxy.
Suitable hydrocarbyl substituents for each of R2, R3, R4 and R6 as appropriate per above include saturated (alkyl), unsaturated (e. g., alkenyl) straight- or branched-chain or cyclic hydrocarbons of up to 16 carbon atoms, preferably saturated hydrocarbons which, in the case of R2, R3 and R4 are optionally substituted by 1-5 hydroxy and/or lower alkoxy groups.
Where the group is unsaturated, there typically are 1-3 unsaturated bonds. Examples of optionally substituted groups include methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 1-(hydroxymethyl)-ethyl, propyl, isopropenyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutenyl, 2-, 3- and 4-hydroxybutyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2- and 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, cyclohexyl and 2-methoxyethyl. "Acyl" typically is alkanoyl and benzoyl. Examples of optionally substituted acyl groups are the acetyl, methoxyacetyl, propionyl, 2-hydroxypropionyl, butyryl, 2,3-dihydroxybutyryl, benzoyl and valeryl groups: examples of optionally substituted acylalkylene groups include the phenacyl or p-phenylphenacyl groups, which can be, for example, alkyl (e.g. of 1-4 C-atoms)- or halogen (F, C1, Br, I)-substituted in the phenyl ring (e. g., 1-2 times), acetonyl, 2-oxobutyl, 2-oxopentyl, 2-oxohexyl, etc.
Preferred are hydrocarbyl and acyl groups of 1-7 carbon atoms and 1-4 hydroxy groups.
In X (as well as in R3 and/or R4) the number of the OH and/or lower alkoxy groups also is 1-5p the number of interrupting oxygen (oxa) atoms in X is typically 1-7 and, of course, the oxa atoms are non-adjacent.
R6 can also stand for C6-10 aryl or C6_10 ar-C1_4 alkyl, e.g., phenyl or benzyl.
Lower alkoxy groups throughout are to contain in each case 1-4 carbon atoms and encompass, e.g., in particular, methoxy and ethoxy groups but also propoxy and butoxy.
' ' 1341 176 - 12 a-Throughout, unsubstituted alkyl groups of 1-7 carbon atoms are preferred, such as, for example, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl groups. Furthermore preferred are mono- and polyhydroxy-substituted alkyl groups of 2-7 carbon atoms and 1-5, preferably 1-4 hydroxy groups, such as, for example, 2- and 3-hydroxypropyl, 1,3-dihydroxy-isopropyl, 1-(hydroxymethyl)ethyl, bis- and tris-(hydroxymethyl)methyl, 2,3-dihydroxy-1-hydroxymethyl-propyl, 2,3,4,5,6-pentahydroxyhexyl and, preferably, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 2,3-dihydroxypropyl, and 2,3,4-trihydroxybutyl.
Furthermore preferred are alkyl groups of 5-23 carbon atoms interrupted by oxygen atoms, e.g..2-[(,e~ -methoxy-, ethoxy- , mono-, di-, tri-, tetra-, penta-, hexa-(ethoxy)Jethyl or 3-[Cad-methoxy-, ethoxy-, mono-, ..., hexa(propoxy)Jpropyl.
When R3 and R4 represent jointly with the nitrogen atom a saturated five- or six=membered ring optionally containing a further hetero atom, e.g., N, O or S, preferably N or O, ~ R3 -N ~ R4 stands preferably for pyrrolidine, piperidine, morpholine or piperazine.
In case R~ stands for a straight-chain or branched alkylene chain containing a COOR1 group at the end, such chain comprises 1-4 carbon atoms; the methylene group is preferred.
The alkylene chain (K) to which the second macrocycle I' is linked carries at the ends optionally carbonyl groups (-CO-K-CO-) and contains 2-20 carbon atoms. This chain can be interrupted by one or several (e. g., 1-7) oxygen atoms) and/or carboxymethylimino 13 41 i groups) and can be substituted by one or several (e. g., 1-5) hydroxy, lower alkoxy and/or carboxy-lower alkyl group(s). Lower alkoxy and lower alkyl groups are to contain respectively 1-4 carbon atoms and comprise, in particular, methoxy, ethoxy, methyl and ethyl groups.
K is a straight- or branched-chain alkylene group interrupted, if desired, by one or several oxygen atoms and/or carboxymethylimino groups, and optionally substituted as described, can contain 2-20 carbon atoms and optionally 2-4 oxa atoms and/or 1-3 carboxymethyliminogroups. Furthermore, the alkylene chain K can be substituted by 1-5 hydroxy, alkoxy or carboxy-lower alkyl groups.
Examples of K are:
-(CH -CH -0-CH -CH )-, -(CH -0-CH ) -, -(CH2)2-, -CHZ-0-CH2-, -(CH2)4-. 2 2 2 2 2 2 2 -CH -CH -(0-CH -CH ) -, -CH -CH -(0-CH -CH ) -, -(CHZ-0-CH2)3-. 2 2 2 2 3 2 2 2 2 4 -CH2 CH-.
OH
-~H-~H-, -CH2-i-, -CH2-~H-iH-CHZ.
~H2 ~H2 ~H2 COOH COOH COOH
. 1341 1 76 The alkylene group contained in R5 can be straight-chain, branched, cyclic, aliphatic, aromatic or arylaliphatic and can contain up to 20 carbon atoms, Straight-chain mono- to hexamethylene groups are preferred, as well as C1-C4-alkylenephenylene groups.
If the alkylene group contains a phenylenoxy group then the latter is preferably linked in the p-position via a methylene group to the -CH-group of the basic skeleton of the compound of general Formula I. The mentioned aromatic nature of an R5 alkylene group will be derived from the mentioned phenylenoxy, phenylene, and/or phenylenimino groups. Typically, the R5 chain can contain up to 4 of the mentioned interrupting groups, e.g., oxa, phenylenoxy, etc.., and 1-5 of the mentioned substituents.
Preferred functional groups present at the end of the R5-alkylene group are, for example, the benzyl ester, ethyl ester, tert-butyl ester, amino, C1-C6-alkylamino, aminocarbonyl, hydrazine, hydrazino-carbonyl, maleimido, methacrylamido, methacryloyl-hydrazinocarbonyl, maleimidamidocarbonyl, halo, mercapto, hydrazinotrimethylenehydrazinocarbonyl, aminodimethyl-eneamidocarbonyl, bromocarbonyl, phenylenediazonium, isothiocyanate, semicarbazide, or thiosemicarbazide group.
For explanatory purposes, several selected R5 substituents will be set forth below:
0y _CH2_C6H4-0(CH2)3-N ~ ~ -CH2-C6H4-0(CH213NH~C
I
-CHZ-CSH;-0-CHZ-C02GH2C6H~, -CHZ-CSN4-0(CH2)5COZCH2CSFi5, 0 -CHZ-C6H~-0(CH2)SCONHNH2, -CH2-C6H4-CONHNH~ , -C~z-C6H4-0(CH2)4-SH, N -C H -0(CH 1 NHNH , -CH2-CSH4-OlCH2)5-CO~IH-N ~ , -CHZ-C6H4-0(CNZ)38r, -CH2-CSH4-0(CHZ)SCONHNH-(CH2)3-NHNH2, -CH2-NHNHZ, -CHZ-SH, -CH2CONHNH2, -(CH2)3SH, -CHZ-C6H4-0-CH2COBr, -CSH4NHCOCH28r, II -CH -C H -NN , -C H -N , -C H NHCS, -CH2-C6H4-OCH2-C-NH-(CHZ)ZNH2, 2 6 4 2 6 4 2 6 4 II CH ) -S-SJ ~ ~I , -NHCO-NH-NH2, -NHCS-NH-NHZ, -CH2-C6H4-NH-C-( 2 2 ~D~ II
-CH -C H -0-CH2-Ct!-CH2, -CHZ-C6H4-0-CH2-IC-NH-(CH21~0-C-NHNH2, -CH -C6H;-0-CH2-CHOH-CHZ-NH(CH2))0-IC-NHNH2, -OCH2-C-N-CH2-(CHOH)4-CHZOH, -CH2-CH-CH2, -CH2-0-(CHZ)3-N ~, -CH2-0-(CH2)~-SH, I
-CH2-D-(CHZ)3-NHNHZ, -CHZ-0-CHZ-IC-NH-NHZ, -CHZ-0-CH2-CH2-NHZ, H -0-CH -NH-IC-(CH ) -S-S~~N~I , CN -0-CHZ-IC-NH-(CH2)~0-IC-NH-NH2, ,z;
".~i - 16 -., If not all acidic hydrogen atoms are sub-stituted by the central ion, then one, several or all remaining hydrogen atoms) can be replaced by cations of inorganic and/or organic bases or amino acids.
Suitable inorganic cations are, for example, the .s lithium ion, the potassium ion, the calcium ion and, in particular, the sodium ion. Suitable cations of organic bases are, inter alia, those of primary, secondary or tertiary amines, e.g. ethanolamine, di-ethanolamine, morpholine, glucamine, N,N-dimethyl-' glucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of , lysine, of arginine and of ornithine.
The complex compounds can also be linked to macromolecules, preferably to one known to be partic-ularly .accumulated in the organ or organ part to be investigated. Such macromolecules include, fo r example, hormones, dextrans, polysaccharides, polychelones, hydroxyethyl starch, polyethylene glycol, desferriox-amines, bleomycins, insulin, prostaglandins, steroid hormones, amino sugars, amino acids, peptides, such as polylysine, proteins (such as, for example, immuno-globulins and monoclonal antibodies) or lipids (also in the form of liposomes). Conjugates with albumins deserve special mention, such as human serum albumin, with antibodies, such as, for example, monoclonal antibodies specific for tumor-associated antigens or antimyosin.
Instead of the biomolecules; it is also possible to link suitable synthetic polymers, such as poly-ethylenimines. The diagnostic media formed there-from are suited, for example,'for use in tumor and infarction diagnostics. Especially suitable monoclonal antibodies for conjugation are those directed against predominantly cell-membrane-fixed antigens.
Suitable as such antibodies are, for example, monoclonal antibodies and/or their fragments [F(ab)2]
for tumor imaging, directed, for example, against the carcinoembryonal antigen (CEA), human chorionic gonadotropin (S-hCG), or other tumor-fixed antigens, such as glucoproteins. Also suitable, inter alia, are anti-myosin, anti-insulin and anti-fibrin antibodies.
Suitable for liver tests and/or for tumor diagnostics are, for example, conjugates or clathrates with liposomes (used, for instance, as uni-laminar or multilaminar phosphatidylcholine-cholesterol vesicles).
All of these conjugations to macrobio-molecules can be effected fully conventionally.
' 1341 1 76 ._ - is -The macrocyclic compounds of general Formula I are produced in that, in a manner known per se, in compounds of general Formula III
/U~-D1.-IUZ-D2.)S-AI
D5 ~y_R2~ tIII)~
\U;-D4.-(U3-D3.)t-A
wherein Y, A1, A~, Ul, U2, U3, U4, s and t have the meanings given above, D1 , D2 , D3 and D4 have the same meanings as Dl, D2, D3 and D4 but contain, in place of the COORl group, the COOZ group wherein Z means a carboxy blocking group, has the meanings given for D1~, D2~, D3~ and D4~, , and also represents the group R5 -~H-wherein R5 means R5, but without exhibiting a macromolecule B, and R2 has the meanings given for R2, but is not to stand for a macromolecule B or the group CH2-COB, the blocking groups Z are split off and the resultant acids (Rl of general Formula I means hydrogen), if desired (a) are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and subsequently, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids;
or (b) are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and subsequently the thus-obtained metal complexes, in a manner known per se, are linked by way of functional groups contained in the molecule, or by way of R2 or, respectively, by way of the CO-group contained in R' 'to a macrocycle , and, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids;.
or ._ a_.. .~o.;~;.~.«; t. . ~ ~,... . ~. .
(c) are conventionally linked by way of the functional groups contained in the molecule, or by way of R2 or, respectively, by way of the CO-group contained in R2 to a macrocycle /and subsequently are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and thereafter, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids.
Carboxy blocking groups Z that can be used are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)methyl group, as well as trialkylsilyl groups.
Cleavage of the blocking groups Z takes place in a manner known per se, for example by hydrolysis, alkaline saponification of the esters, preferably with an alkali in an aqueous-alcoholic solution at temperatures of 0° to 50° C or, in case of, for example, tert-butyl esters, with the aid of trifluoroacetic acid.
The educts are prepared by cyclizing of two 5"
reactants, one of which is R -substituted, wherein 5" 5' R stands for a substituent convertible into R ;
the thus-obtained cyclic compounds are subsequently reacted, optionally after splitting off blocking groups, with halogen alkanes, halogen esters, halogen acids, halogen ketones, acyl halogenides or acyl anhydrides in order to introduce. the substituent R2.
The cyclization is performed according to methods known in the literature (for example, Org.
Synth. 58 . 86 [1978], Macrocyclic Polyether Syntheses, Springer Publishers, Berlin, Heidelberg,New York, 1982, Coord. Chem. Rev. 3 . 3 [1968], Ann. Chem. 1976 . 916):
one of the two reactants carries at the end of the chain two fugitive groups, the other carries two nucleophiles displacing these fugitive groups.
An example that can be cited is the reaction of end-positioned dibromo-, dimesyloXy-, ditosyloxy- or dialkoxycarbonylalkylene compounds optionally con-taining hetero atoms with end-positioned diaza-alkylene compounds optionally containing additional hetero atoms in the alkylene chain, of which 5"
one of the two reactants is R -substituted.
Nitrogen atoms present are optionally blocked, for example in the form of tosylates, and are liberated _ 22 _ prior to the subsequent alkylation reaction in accordance with methods known from the literature.
If diesters are used in the cyclization reaction, the thus-obtained diketo compounds must be reduced by methods known to those skilled in the art, for example with diborane.
The subsequent alkylation takes place with halogen ketones, halogen esters, halogen acids or halogen alkanes which can be substituted by one or several hydroxy or lower alkoxy groups and may contain oxygen atoms) in the chain. Furthermore, the alkyl residue can also contain an end-positioned amino group.
If alkylation takes place with a dihalogenated alkane, compounds of general Formula III are produced having two macrocyclic rings joined by way of a carbon bridge.
Additional methods known from the literature for the synthesis of compounds having more than one ring are, for example, reactions of an amine with a carbonyl compound (e. g. the acid chloride, mixed anhydride, activated ester, aldehyde); of two amine-substituted rings with a dicarbonyl compound (e. g.
oxalyl chloride, glutaric dialdehyde~; of two rings each exhibiting a nucleophilic group with an alkylene com-pound carrying two fugitive groups; in case of terminal acetyls, oxidative coupling (Cadiot, Chodkiewicz in Viehe "Acetylenes", 597-647, Marcel Dekker, New York, 1969). The, chain linking the rings can subsequently be modified by secondary reactions (e. g.
hydrogenation).
The saponification of the ester groups obtained during alkylation with halogen esters, which may be necessary, is performed according to methods known to those skilled in the art (for example with ' ' 1341 176 ' alkaline catalysts, such as alkali or alkaline earth carbonates or hydroxides).
In the alkylation with haloacetic acid, an intermediate product is obtained wherein R2 -CH2X-COON; this product is converted into the monoamide by way of the mixed anhydride with chloroformic acid ester or.with the aid of dicyclohexylcarbodiimide and reaction with a primary or secondary amine of the general formula ~ R3 .
~ R
Examples for suitable amines are: dimethyl-amine, diethylamine, di-n-propylamine, diisopropyl-amine, di-n-butylamine, diisobutylamine, di-sec-butylamine, N-methyl-n-propylamine, dioctylamine, dicyclohexylamine, N-ethylcyclohexylamine, diisopropenyl-amine, benzylamine, aniline, 4-methoxyaniline, 4-dimethylaminoaniline, 3,5-dimethoxyaniline, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethyl-piperazine, N-(2-hydroxyethyl)piperazine, N-(hydroxy-methyl)piperazine, piperazinoacetic acid isopropylamide, N-(piperazinomethylcarbonyl)morpholine, N-(piperazino-methylcarbonyl)pyrrolidine, 2-(2-hydroxymethyl)-piperidine, 4-(2-hydroxyethyl)piperidine, 2-hydroxy-methylpiperidine, 4-hydroxymethylpiperidine, 2-hydroxy-methylpyrrolidine, 3-hydroxypiperidine, 4-hydroxy-piperidine, 3-hydroxypyrrolidine, 4-piperidone, 3-pyrroline, piperidine-3-carboxylic acid amide, piper-idi.ne-4-carboxylic acid amide, piperidine-3-carboxylic acid diethylamide, piperidine-4-carboxylic acid di-methylamide, 2,6-dimethylpiperidine, 2,6-dimethyl-morpholine, N-acetylpiperazine, N-(2-hydroxypropionyl)-piperazine, N-(3-hydroxypropionyl)piperazine, N-(methoxyacetyl)piperazine, 4-(N-acetyl-N-methylamino)-piperidine, piperidine-4-carboxylic acid (3-oxapentamethylene)amide, piperidine-3-carboxylic acid (3-oxapentamethylene)amide, N-(N',N'-dimethyl-carbamoyl)piperazine, pyrazoline, pyrazolidine, imid-azoline, oxazolidine, thiazolidine, 2,3-dihydroxypropyl-amine, N-methyl-2,3-dihydroxypropylamine, 2-hydroxy-1-(hydroxymethyl)ethylamine, N,N-bis(2-hydroxyethyl)amine, N-methyl-2,3,4,5,6-pentahydroxyhexylamine, 6-amino-2,2-dimethyl-1,3-dioxepin-5-ol, 2-hydroxyethylamine, 2-amino-1,3-propanediol, diethanolamine, ethanolamine.
The polyhydroxyalkylamines can advantageously be used for the reaction also in the blocked form, for ex=
ample as O-acyl derivatives or as ketals. This is applicable especially if these derivatives can be pro-duced more conveniently and cheaply than the poly-hydroxyalkylamines proper. A typical example is 2-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol, the acetonide of 1-amino-2,3,4-trihydroxybuta~e, produced in accordance with DOS 31 50 917 published June 30, 1983.
The subsequent removal of the blocking groups does not entail any problems and can take place, for example, by treatment with an acidic ion exchanger in an aqueous-alcoholic solution.
Acylation is performed with a corresponding acyl derivative, especially with an acyl halogenide or anhydride. When using anhydrides or halogenides of di-or polycarboxylic acids, then compounds of general Formula III are obtained wherein the two macrocyclic rings are linked in the manner of an amide by way of a carbon bridge.
Suitable as substituents RS~~ convertible into the substituents R5 exhibiting at the end a functional group suited for linkage to a macromolecule are, inter alia, hydroxy and nitrobenzyl, hydroxy and carboxy-alkyl, as well as thioalkyl residues of up to 10 carbon ~~ ~ ,s..J .
atoms. They are converted in accordance with methods disclosed in the literature and known to those skilled in the art CChem. Pharm. Bull. 33 . 674 [1985], Compendium of Org. Synthesis vol. 1-5, Wiley and Sons, Inc.) into the desired substituents (e.g. with the amino, hydrazino, hydrazinocarbonyl, methacryloyl-hydrazinocarbonyl, maleimidamidocarbonyl, halogeno, halogenocarbonyl, mercapto group as the functional group); in case of the nitrobenzyl residue, a catalytic hydrogenation (e. g. according to P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press 1967) must first be performed to obtain the aminobenzyl derivative.
Examples for the conversion of hydroxy or amino groups bound to aromatic or aliphatic residues are the reactions performed in anhydrous, aprotic solvents, such as tetrahydrofuran, dimethoxyethane or dimethyl sulf-oxide in the presence of an acid captor, such as, for example, sodium hydroxide, sodium hydride or alkali or alkaline earth carbonates, e.g. sodium, magnesium, potassium, calcium carbonate, at temperatures of between 0° C and the boiling point of the respective solvent, but preferably between 20° C and 60° C, with a substrate of general Formula IV
W-L-Fu (IV) wherein W is a nucleofugic entity, such as, for ex-ample, C1, Br, I, CH3C6H4S03 or CF3S03; L is an aliphatic, aromatic, arylaliphatic, branched, straight-chain or cyclic hydrocarbon residue of up to 20 carbon atoms; and Fu is the desired end-positioned functional group.
' 1341 1 76 Examples of compounds of general Formula IV
are Br(CH2)2NH2, 8r(CHZ)30H, BrCH2C00CH3, BrCH2C02tBu, Br(CH2)4C02C2H5, BrCH20COBr, 8rCH2CONH2, C1CH2COOC2H5, BrCH2CONHNH2, BrCH2-CH-CH2, CF3S03(CHZ)3Br, 8rCH2C=CH, BrCH2CH=CH2.
Conversions of carboxy groups can be conducted, for example, according to the carbodiimide method (Fieser, Reagents for Organic Syntheses 10, 142) via a mixed anhydride (Org. Prep. Proc. Int. 7 . 215 [1975]) or via an activated ester (Adv. Org. Chem. Part B, 472).
The compounds of general Formula I wherein Rl is a hydrogen atom represent complex-forming com-pounds. They can be isolated and purified or, without isolation, can be converted into metal complexes of general Formula I wherein at least two of the substi-tuents Rl mean a metal ion equivalent.
The metal complexes of this invention are prepared as disclosed in the references cited above by dissolving or suspending the metal oxide or a metal salt (e. g. the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 in water and/or a lower alcohol (such as methanol, ethanol or iso-propanol) and reacting with a solution or suspension of the equivalent amount of the complex-forming acid of general Formula I wherein Rl means a hydrogen atom, and subsequently, if desired,'substituting any present acidic hydrogen atoms of acid groups by cations of inorganic and/or organic bases or amino acids.
Neutralization takes place in this process with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium or lithium and/or with the aid of organic bases, such as, _ 1341 176 inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as alkaline amino acids, such as, for example, lysine, arginine and ornithine.
In order to prepare the neutral complex compounds, it is possible, for example, to add to the acidic complex salts, in an aqueous solution or sus-pension, such an amount of the desired bases that the neutral point is reached. The resultant solution can then be concentrated to dryness under vacuum. It is frequently advantageous to precipitate the thus-formed neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others) and thus to obtain crystallized products which can be readily isolated and easily purified. It proved to be particularly advantageous to add the desired base to the reaction mixture as early as during the complex formation and thereby to save a process step.
If the acidic complex compounds contain several free acidic groups, it is often advantageous to prepare neutral mixed salts containing inorganic as well as organic cations as counterions.
This can be done, for example, by reacting the complex-forming acid in an aqueous suspension or solution with the oxide or salt of the element yielding the central ion and half the amount,required for neutralization,of an organic base; isolating the thus-formed complex salt; purifying same if desired; and then combining same, for complete neutralization, with the needed amount of inorganic base. The sequence of adding the bases can also be reversed.
1341 1 7fi ' Alkaline groups can be converted into pharmaceutically compatible salts with inorganic and/or organic acids.
Examples for suitable inorganic bases are lithium, sodium and potassium hydroxide. Organic bases are, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as alkaline amino acids, such as, for example, lysine, arginine and ornithine.
Inorganic acids, e.g, hydrochloric acid, and organic acids, e.g. citric acid, can be used for forming the salt with alkaline groups.
Conjugate formation can be effected, for ex-ample, by way of a carboxy group of the complex compound or by way of the functional group, as defined hereinabove, present at the end of the C1-C20-alkylene group of sub-stituent R5. When forming the conjugate of acids with macromolecules, several acid residues can be bound to the latter. In this case, several central ions can be bound to a macromolecule.
Coupling to the desired macromolecules like-wise takes place according to conventional methods as disclosed, for example, in Rev. Roum. Morphol. Embryol.
Physiol., Physiologie 1981, 18 . 241 and J. Pharm. Sci.
68 . 79 (1979), for example by reacting the nucleophilic group of a macromolecule, such as the amino, phenol, sulfhydryl, aldehyde or imidazole group, with an activated derivative of the complexing compound. Ex-amples of activated derivatives are monoanhydrides, acid chlorides, acid hydrazides, mixed anhydrides (see, for example, G.E. Krejcarek and K.L. Tucker, Biochem.
Biophys. Res. Commun. 1977, 581), activated esters, nitrenes or isothiocyanates. Conversely, it is also possible to react an activated macromolecule with the .... ..r~W .~... ~.~~*...., ..*,~,..,.. .*_..., . *. *....*.... ....:.... a ..
. . ..
- 1341 17fi complex-forming acid. For conjugation with proteins, also suitable are substituents having, for example, the structure C6H4,N2, C6H4NHCOCH2, C6H4NHCS, or C6H40CH2C0.
Conjugation of the complex-forming acid with dextrans and dextrins also takes place in accordance with conventional methods, e.g. by activation of the polysaccharides with cyanogen bromide and subsequent reaction with amino groups of the complex-forming acid.
When using complex compounds which contain radioisotopes, they can be prepared according to the methods described in "Radiotracers for Medical Applica-tions", vol. 1, CRC-Press, Boca Raton, Florida.
All starting materials used in the mentioned conventional reaction are known or conventionally preparable from known starting materials.
The pharmaceutical agents of this invention are likewise prepared conventionally by suspending or dissolving the complex compounds of this invention --optionally while combining them with the additives customary in galenic pharmacy -- in an aqueous medium and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as, for ex-ample, tromethamine), small amounts of complexing agents (such as, for example, diethylenetriaminepenta-acid acid) or, if required, electrolytes, e.g. sodium chloride or, if needed, antioxidants, such as, for example, ascorbic acid.
If suspensions or solutions of the agents of this invention in water or physiological saline solution are desirable for enteral administration or other pur-poses, then they are mixed with one or several of the auxiliary agents customary in galenic pharmacy (for example, methylcellulose, lactose, mannitol) and/or tensides (for example lecithins, and those sold under the trademarks "Tween", "Myrj") and/or flavoring materials) to improve taste (e. g. ethereal oils).
_;
.._.~..,..a.,'~~~!Y!0.::-.~.::~~~.: ~..~NIGn~S:v,.... ...... ..
' ' 1341 176 In principle, it is also possible to prepare the pharmaceutical agents of this invention even without isolating the complex salts. In any event, special care must be directed toward effecting chelate forma-tion in such a way that the salts and salt solutions according to the invention are practically devoid of uncomplexed, toxically active metal ions.
This can be ensured, for example, with the aid of dye indicators, such as xylenol orange, by control titrations during the manufacturing process. Therefore, the invention also relates to processes for the produc-tion of the complex compounds and their salts. Purifica-tion of the isolated complex salt remains as a final safety measure.
The pharmaceutical agents of this invention preferably contain 1 umol to 1 mol per liter of the complex salt and are normally administered in doses amounting to 0.001 - 5 mmol/kg. They are intended for entral and parenteral administration.
The agents of this invention fulfill the variegated requirements for suitability as contrast media for nuclear spin tomography. Thus, they are excellently suited for improving the information content of the image obtained with the aid of the nuclear spin tomograph upon oral or parenteral administration, by increasing the signal intensity. Furthermore, they exhibit the high efficacy necessary to introduce into the body a minimum amount of burdening foreign substances, and they show the good compatibility necessary for main-taining the noninvasive character of the examinations.
The good water solubility of the agents of this invention makes it possible to prepare highly concentrated solutions, thus maintaining the volume load on the circulation within tolerable limits and compensating for dilution by body fluids. Furthermore, the agents of the present invention not only exhibit high stability in vitro, but also a surprisingly high stability in vivo, so that a release or exchange of the ions -- toxic per se -- which are not bound in a co-y valent fashion in the complexes takes place only extreme-ly gradually within the time period during which the novel contrast media are again completely eliminated.
In general, the agents of this invention are dosed, for use as NMR diagnostics, in quantities of 0.001 - 5 mmol/kg, preferably 0.005 - 0.5 mmol/kg.
Details of usage are discussed, fox example, in H.J. Weinmann et al., Am. J. of Roentgenology 142 . 619 (1984), e.g., analogously to Gd-DTPA.
Extremely low doses (below 1 mg/kg) of organ-specific NMR diagnostics are .usable,: for example, for the detection of tumors and of cardiac infarctions. Fur-thermore, the complex compounds of this invention can be utilized advantageously as shift reagents.
On account of their favorable radioactive properties and the good stability of the complex com-pounds contained therein, the agents of this invention are also suitable as radiodiagnostic media. Details of their use and dosage are described, for example, in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.
Another imaging method with radioisotopes is positron emission tomography, utilizing positron-emitting isotopes, such as, for example, 43Sc, 44Sc, 52Fe, 55Co and 68Ga. (Heiss, W.D., Phelps, M.E., "Positron Emission Tomography of Brain", Springer Publishers, Berlin, Heidelberg, New York, 1983.) The compounds of this invention can also be used in radioimmunotherapy. This procedure differs from the corresponding diagnostics only by the amount and type of radioactive isotope employed. The objective herein is destruction of tumor cells by high-energy shortwave radiation with as short a range as possible.
The specificity of the antibody employed is herein of decisive importance since unspecifically localized anti-body conjugates lead to destruction of healthy. tissue.
The antibody or the antibody fragment of the antibody metal complex of this invention serves for transporting the complex,in an immune-specific way for the respective antigen, to the target organ where the metal ion selected on account of its cytocidal proper-ties can emit radiation causing lethal damage to the cells. Suitable S-emitting ions are, for example, 46Sc~ 47Sc, 48Sc, ~2Ga and ~3Ga. Suitable a-emitting ions exhibiting low.~half-life values are, for example, 211Bi~ 212Bi~ 213Bi and 214Bi,- wherein 212Bi is preferred.
In the in vivo administration of the therapeutic agents of this invention, these agents can be given together with a suitable excipient, e.g. serum or physiological sodium chloride solution and together with another protein, such as, for example, human serum albumin. The dose in this connection is dependent on the type of cellular disorder, the metal ion used, and the type of imaging method.
The therapeutic media of this invention are administered parenterally, preferably intravenously.
See, e.g., R.W. Kozak et al, Trends in Biotechnology (TIBTEC), October 1986, 262.
The agents of this invention are excellently suited as X-ray contrast media; in this connection, it should be emphasized, in particualr, that their use does not bring about any indications of anaphylaxis-type reactions in biochemical-pharmacological tests. They are especially valuable for digital subtraction techniques on account of their favorable absorption properties in regions of higher tube voltages.
In general, the agents of this invention are used, when administered as X-ray contrast media, in doses analogous to, for example, meglumine diatrizoate in amounts of 0.1 - 5 mmol/kg, preferably 0.25 - 1 mmol/kg.
Details of usage of X-ray contrast media are discussed, for example, in Barke, "Roentgenkontrastmittel"
[X-Ray Contrast Media], G. Thieme, Leipzig(1970),and P. Thurn, E. Btlcheler, "Einfuehrung in die Roentgen-diagnostik" [Introduction to X-Ray Diagnostics], G. Thieme, Stuttgart, New York(1977).
The agents according to the invention are also 20. suitable -- since their acoustic impedance is higher than that of body fluids and tissues -- as contrast media for ultrasonic diagnostics, especially in the form of suspensions. They are generally used in doses amounting to 0.1 - 5 mmol/kg, preferably 0.25 - 1 mmol/kg.
Details of the use-of ultrasonic diagnostica are disclosed, for example, in T.B. Tyler et al., Ultrasonic Imaging 3.323 (1981), J.I. Haft, "Clinical Echocardiography", Futura, Mount Kisco, New York 1978, and G. Stefan, "Echokardiographie" G. Thieme, Stuttgart/
New York, 1981.
In summation, novel complex-forming compounds, metal complexes, and metal complex salts are provided, opening up new possibilities in diagnostic and therapeutic medicine. This development appears to be valuable, above all, in connection with the evolution of novel imaging methods in medical diagnostics.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
.4 The synthesis of starting materials will be described below by way of example, beginning with a cyclization reaction:
(a) 1-Benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane At 100° C under agitation, 145 g of N,N-bis[2,2'-(p-tolylsulfonyloxy)]ethanebenzylamine, dissolved in 900 ml of dimethylformamide is added dropwise within 3 hours to a solution of. 164.6 g o.f N,N' ,N' '-tris (p-tolyl-sulfonyl)diethylenetriamine-N,N " -disodium salt in 2.16 1 of dimethylformamide. Then, under agitation at 80° C, one liter of water is added dropwise, and the mixture is further stirred for 18 hours at room tempera-ture, whereafter it is cooled to 0° C and the precip-itate is suctioned off, washed with a small amount of ice-cold ethanol and dried at 15 torr and 60° C, yielding 175 g of the title compound.
Alternative Route 1 An analogous method for preparing tetraazacyclo-dodecane derivatives is found in M. Hediger and T.A.
Kaden, Helv. Chim. Acta 66 . 861 (1983).
At 80-85° C, 30.94 g of N,N',N " -tris(p-tolyl-sulfonyl)diethylenetriamine-N,N " -disodium salt and 28.12 g of N-bis(2-methanesulfonyloxyethyl)triphenyl-methylamine are stirred with 530 ml of dimethylformamide for 20 hours, then cooled off and stirred into a solu-tion of 30 g of potassium carbonate in 5 1 of ice water.
The precipitate is suctioned off, the filter cake is washed with 0.5 1 of water, and dried at 20oC under vacuum at 150 torr. For purification, the product is dissolved in 230 ml of chloroform and 5 ml of triethylamine, filtered, concentrated to 200 ml under vacuum, and 1341 1 7fi the solution is combined under boiling heat with 250 ml of ethyl acetate. The mixture is allowed to cool off overnight and the thus-precipitated crystals are suctioned off, yielding 22.18 g of 1,4,7-tris(p-tolylsulfonyl)-10-triphenylmethyl-1,4,7,10-tetraazacyclododecane, mp 185-188 C (decomposition).
In order to split off the trityl blocking group, 31.4 g of the tritosyl-trityl derivative pr-epared in this way is stirred in a mixture of 100 ml of glacial acetic acid, 75 ml of water, and 300 ml of dioxane for one hour at 80 C. Then the mixture is exhaustively concentrated~under vacuum at 60,C, diluted with 300 ml of ice water and combined with 40 ml of 11N sodium hydroxide solution (pH above 12). This mixture is shaken with 300 ml of chloroform, the phases are separated, the aqueous phase is extracted twice with respectively 100 ml of chloroform, and the combined ~,t, chloroform phases are dried over sodium sulfate and evaporated under vacuum. The frothy residue is treated with 300 ml of diethyl ether, thus bringing about.
crystallization. The mixture is suctioned off, the crystals~are dried under vacuum at 60 C and 150 torr, and the yield is 21 g of 1,4,7-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane, mp 202-203 C.
The thus-obtained tritosyl compound (21 g) is dissolved in 200 ml of dimethylformamide, the solution is combined in succession with 13.71 g of anhydrous potassium carbonate, 4.95 g of sodium iodide, and 7.92 g of benzyl bromide, and agitated for.5 hours at 100 C, then cooled to 20 C, and the mixture is stirred into 4 1 of ice water, suctioned off, and the residue dissolved in 2 1 of dichloromethane. The solution is extracted with 100 ml of water, dried over sodium sulfate and evaporated under vacuum.
' 1341 1 76 The residue is dissolved under boiling heat in 500 ml of acetonitrile, allowed to crystallize over-night, suctioned off, and the crystals are dried at 50° C and 150 torr, yielding 16.20 g of 1-benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraaza-cyclododecane, mp 217-219° C.
(b) N-Benzyl-1,4,7,10-tetraazacyclododecane 150 g of 1-benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane is heated with 900 ml of HBr/acetic acid (40$ strength) and 125 g of phenol for 16 hours to 50° C. After cooling to 20° C, the mixture is diluted with one liter of ether, cooled to -5° C, and the thus-precipitated crystals are suctioned off.
In order to isolate the free base, the product is dis-solved in 500 ml of 4N sodium hydroxide solution, saturated with potassium carbonate, and repeatedly ii!
extracted with chloroform, dried over magnesium sulfate, and evaporated under vacuum. Yield: 39 g of the title compound as a light-yellow, viscous oil. A sample was characterized as the trihydrochloride: mp 210° C
(under decomposition).
Alternative Route 2 A solution of 11.2 g of 1,4,7,10-tetraazacyclo dodecane in 900 ml of tetrahydrofuran is combined at -20° C with 58 ml of triethylamine and, under agita tion, a solution of 16.2 ml o,f benzoyl chloride in 280 ml of tetrahydrofuran is added dropwise thereto within 3 hours. During this step, the room temperature rises to slightly above -10° C.
The mixture is then agitated for 16 hours at 0-10° C, the precipitate is filtered off, and the solution is evaporated under vacuum. The residue is chromato-graphed on 1 kg of silica gel and eluted with a ' - 1341 1 7~
solution of dioxane-water-ammonia (8:1:1). The fractions uniform in accordance with TLC are combined, evaporated, dissolved in dichloromethane, and filtered to eliminate a slight turbidity, and the solution is evaporated, thus obtaining 19.60 g of 1,4,7-tribenzoyl-1,4,7,10-tetraazacyclododecane, mp 120-125 C.
11.5 g of the thus-obtained tribenzoate is stirred in 150 ml of dimethylformamide with 8.3 g of anhydrous potassium carbonate, 3.0 g of sodium iodide, and 7.2 ml of benzyl bromide for 18 hours at 100 C.
The mxiture is then filtered, the solution evaporated under vacuum, the residue stirred twice with respectively 50 ml of hexane, and decanted. The hexane phases are discarded. For purification, the product is dissolved in dichloromethane and chromatographed with dichloro-methane-methanol (37:3) over 0.5 kg of silica gel, thus obtaining 10.2 g of 1,4,7-tribenzoyl-10-benzyl-1,4,7,10-tetraazacyclododecane, mp 105-109 C.
In order to split off the benzoyl groups, this product (2.87 g) is dissolved in 290 ml of tetrahydro-furan, combined with 11.2 g of potassium tert-butylate, and heated under reflux for 48 hours. The mixture is filtered, evaporated under vacuum, the residue combined under ice cooling with 100 ml of water and extracted three times with respectively 50 ml of dichloromethane.
The combined dichloromethane phases are shaken with 10 ml of water, dried over sodium sulfate, and evaporated under vacuum. The initially oily residue crystallizes very gradually and is triturated with 20 ml of hexane.
After suctioning off and drying, 1.15 g of N-benzyl-1,4,7,10-tetraazacyclododecane is obtained, mp 75-78 C.
1341 1 7~
(c) 1-Benzyl-4,7,10-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane At 0° C, a solution of 131.8 g of N-benzyl-1,4,7,10-tetraazacyclododecane in 1.5 1 of dichloro-methane is combined in succession with 200 g of triethylamine and, within 2 hours, with 260 g of bromoacetic acid ethyl ester. The mixture is stirred for 16 hours at room temperature, shaken with 5$
strength sodium carbonate solution and brine, dried over magnesium sulfate, and evaporated under vacuum.
The residue.is dissolved in 200 ml of chloroform and filtered over 2 kg of silica gel, eluting with one liter of chloroform-methanol (95:5). Yield: 210 g of the title compound as a viscous oil.
(d) N,N',N " -Tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane ____________________________________ 100 g of 1-benzyl-4,7,10-tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved in 0..5 1 of acetic acid and 0.5 1 of ethyl acetate, combined with 5 g of palladium on carbon (10~), and shaken under hydrogen for 5 hours. The mixture is removed from the catalyst by filtration, concentrated under vacuum, the residue is dissolved in one liter of chloroform, shaken with 100 ml of saturated soda solution and 100 ml of brine, dried, and evaporated under vacuum. The residue is purified by bulb tube distillation at 10 3 torr and 120° C, yielding N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane as a viscous, light-yellow oil.
Yield: 65 g.
IR (Film): 3400, 2935, 2878, 1738/cm.
1341 1 ~6 Example 1 Gadolinium(III) Complex of 1,4,7,10-Tetraazacyclo-dodecane-N,N',N " -triacetic Acid 40.25 g (100 millimoles) of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 0.5 1 of ethanol, combined with 100 ml of 3N sodium hydroxide solution, and stirred at 20° C
for 5 hours. The mixture is concentrated to 70 ml under vacuum, combined with 300 ml of water, and 2N hydro-chloric acid is added dropwise thereto up to a pH of 6.
Then the mixture is combined with 33.44 g (100 mmol) of gadolinium acetate and stirred for 3 hours at 60° C.
The solution is then first passed over an anion ex-changer "Amberlite"~'LRA 410 and then the aqueous eluate is passed over a ca~ion exchanger "Amberlite" IRC 50.
The mixture is eluted with water and the eluate evap-orated under vacuum. After drying of the residue, 35.04 g (70$ of theory) of the title compound is obtained as a colorless powder.
Anal~rsis: C14H23GdN406 (600.61) C 33.59 H 4.63 Gd 31.41 N 11.19 (calc.) 33.31 4.59 31.18 11.28 (found) Example 2 Gadolinium(III) Complex of N-(2,3-Dihydroxy-N-methyl-propylcarbamoylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N " ,N "'-triacetic Acid 55 g of N-(2,3-dihydroxy-N-methylpropyl-carbamoylmethyl)-N',N " ,N "'-tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved inØ5 1 of ethanol, combined with 96 ml of 3N sodium hydroxide solution, and stirred at 20° C for 3 hours, then concentrated under vacuum, combined with 300 ml of water and adjusted to pH 6 with 2N hydrochloric acid. To this solution is added 31.94 g of gadolinium acetate and the mixture is stirred for 18 hours at 50° C, then passed over an anion exchanger "Amberlite"
IRA 410, and subsequently the aqueous eluate is passed over a cation exchanger "Amberlite" IRC 50. The wj eluate is evaporated under vacuum and dried, thus obtaining 47.14 g (73$ of theory) of the title compound as a colorless powder.
Analysis: C20H34GdN509 (645.77) C '37.20 H 5.31 Gd 24.35 N 10.85 (calc.) 37.52 5.19 24.09 10.87 (found) The starting material for preparing the title compound according to Example 2 is obtained as follows:
(a) N,N',N " -Tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic Acid 20 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 300 ml of dichloromethane, combined with 10.40 g of triethyl-amine, and then at 0° C a solution of 4.40 g of chloroacetic acid in 100 ml of dichloromethane .
is added dropwise thereto and the mixture agitated at room temperature for 20 hours. For working-up purposes, the mixture is divided between dich.lbro-methane and phosphate buffer, pH 6, dried over magnesium sulfate, and evaporated under vacuum, yielding 23 g of the desired compound as a viscous oil.
(b) N-(2,3-Dihydroxy-N-methylpropylcarbamoylmethyl)-N',N " ,N "'-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane At 0° C, 10.5 g of triethylamine and then 14 g of chloroformic acid isobutyl ester are added dropwise to a solution of 48.86 g (100 mmol) of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid in 500 ml of dichloromethane. The mixture is stirred for one hour at 0° C and then a solution of 10.52 g of N-methylamino-2,3-propanediol in 100 ml of chloroform is added dropwise thereto and the mixture is stirred at room temperature for 2 hours. Subsequently the mixture is shaken with sodium bicarboante solution and brine, dried over magnesium sulfate, and evaporated under vacuum. For purification, the chloroform solution of the residue is filtered over 500 g of silica gel, yielding 55 g of the title compound.
r , 1341 1 7~
Example 3 Gadolinium(III) Complex of N-(N-Ethylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 24 g of N-(N-ethylcarbamoylmethyl)-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 250 ml of ethanol, combined with 47 ml of 3N sodium hydroxide solution, and stirred for 3 hours.at 20° C, then concentrated under vacuum, combined with 150 ml of water, and adjusted to pH 6 with 2N hydrochloric acid. The mixture is combined with 15.55 g of gadolinium acetate and stirred at 60° C
for 5 hours. The solution is then purified by way of ion exchangers as described in the preceding examples, thus obtaining 20.39 g of the title compound as a colorless powder.
Analysis: C18H30GdN507 (585.72) C 36.91 H 5.16 Gd 26.85 N 5.16 (calc.) 36.98 5.28 26.58 5.07 (found) Preparation of the starting material:
g (51.2 mmol) of N,N',N " -tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid (see Example 2a) is dissolved in 200 ml of dichloromethane, combined at 0° C with 5.40 g of 25 triethylamine, and subsequently with 7 g of chloroformic acid isobutyl ester. The mixture is stirred for one hour at 0° C and then a solution of 2.31 g of ethyl-amine in 20 ml of dichloromethane is added dropwise thereto. The mixture is stirred for 2 hours at room temperature, shaken with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and r evaporated to dryness under vacuum. For purification, the dichloromethane solution of the residue is filtered over 200 g of silica gel, thus obtaining 24 g of N- (N-ethylcarbamoylmethyl) -N' ,N" ,N" '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane.
Example 4 Gadolinium(III) Complex of N-Acetyl-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N " -tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 mlof:dichloromethane, combined with 10 ml of pyridine, 100 mg of 4-dimethyaminopyridine, and 2.50 g of acetyl chloride, stirred at room temperature for 5 hours, combined with 1 ml of ethanol, and evap-orated under vacuum. The residue is stirred at room temperature for 5 hours with 40 ml of 1N sodium hydroxide solution, diluted with 100 ml of water, and a pH is set of 6 with 2N hydrochloric acid. Then 3.34 g of gadolinium acetate is added to the reaction mixture, and the latter is stirred at 60° C for 5 hours and the solution is subjected to purification with ion exchangers (as described in the other examples), thus obtaining 4.23 g of the title compound as a colorless powder.
Analysis: C16H25GdN407 (542.65) C 35.41 H 4.64 Gd 28.98 N 10.32 (calc.) 35.63 4.51 28.73 10.52 (found) 141 1 ~~
Example 5 Gadolinium(III) Complex of N-Ethyl-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 ml of dichloromethane, combined with 2.10 g of triethyl-amine and 3.12 g of iodoethane and, after 2 hours, the mixture is repeatedly extracted with water, dried over magnesium sulfate, and evaporated under vacuum. The residue is stirred for 6 hours with 100 ml of 1N sodium hydroxide solution, then adjusted to pH 6 with 2N
hydrochloric acid, and agitated for 16 hours with 3.34 g of gadolinium acetate at 60° C. The resultant solution is subjected to purification with ion exchangers, thus obtaining 3.70 g of the title compound as a color-less powder.
Analysis: C16H27GdN406 (528.66) C 36.35 H 5.15 Gd 29.74 N 10.60 (calc.) 36.15 5.32 29.70 10.41 (found) Example 6 Gadolinium(III) Complex of N-(2,3-Dihydroxy-1-propyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N','-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 ml of dichloromethane, combined with 4.20 g of triethyl-amine and 2.21 g of 3-chloro-1,2-propanediol, and stirred at room temperature for 16 hours. The mix-ture is shaken with water and evaporated under vacuum.
The residue is stirred for 6 hours with 100 ml of 1N
sodium hydroxide solution, adjusted to pH 6 with 2N
hydrochloric acid, and agitated for 16 hours with 1341 17fi 3.34 g of gadolinium acetate at 50° C. The thus-obtained solution is subjected to ion exchanger purification, yielding 3.62 g of the title compound as a colorless powder.
Analysis: C17H29GdN408 (574.69) C 35.53 H 5.09 Gd 27.36 N 9.75 (calc.) 35.68 5.19 27.03 9.68 (found) Example 7 Gadolinium(III) Complex of N-(2-Aminoethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 2.10 g of triethylamine and 1.22 g of N-(2-chloroethyl)acetamide are added to a solution of 4.30 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 100 ml of dichloro-methane. The mixture is stirred at room temperature for 18 hours, shaken with water, and evaporated under vacuum.
The residue is atirred at 60 °. C 'for= 8 .hours :with 50 .ml of 1N sodium hydroxide solution, adjusted to pH 6 with 2N hydrochloric acid, and stirred for 16 hours with 3.34 g of gadolinium acetate at 50° C. The thus-formed solution is subjected to ion exchanger purification, yielding 3.21 g of the title compound as a colorless powder.
Analysis: C16H28GdN506 (543.68) C 35.35 H 5.19 Gd 28.92 N 12.88 (calc.) 35.17 5.45 28.68 12.81 (found) 1 r 1341 1 7fi Example 8 Bis[Gadolinium(III)] Complex of 1,1'-(1,3-Propylene)-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic Acid A solution of 8.60 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 4.2 g of triethylamine in 200 ml of dichloro-methane is combined with 2.02 g of 1,3-dibromopropane and agitated for 20 hours at room temperature, shaken with water and brine, and evaporated under vacuum. The residue is fitlered with dichloromethane over 150 g of silica gel and evaporated, thus obtaining a viscous oil which is stirred with 60 ml of 1N sodium hydroxide solution for 16 hours, then diluted with 100 ml of water and adjusted to pH 6 with 2N hydrochloric acid.
After adding 6.68 g of gadolinium acetate, the mixture is stirred for 16 hours at 50° C and the solution is purified over anion and cation exchangers, thus obtain-ing 6.56 g of the title compound as a colorless powder.
Analysis: C31H50Gd2N8012 (1041.28) C 35.76 H 4.84 Gd 30.20 N 10.76 (calc.) 35.71 4.58 29.94 10.88 (found) Exam lp a 9 Bis[Gadolinium(III)] Complex of Succinyl-bis(1,4,7,10-tetraazacyclododecane-4,7,1.0-triacetic Acid) A solution of 4.30 'g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 4.20 g of triethylamine in 100 ml of dichloromethane is combined at 0° C dropwise with 1.705 g of succinic acid dichloride, dissolved in 20 ml of dichloromethane, and then the mixture is stirred for one hour at room temperature, shaken with sodium bicarbonate solution _ 48 _ '341 1 ~s and brine, and evaporated under vacuum. The residue is chromatographed on 100 g of silica gel with dichloromethane/ethyl acetate (0-30~).
A viscous oil is obtained which is stirred with 40 ml of 1N sodium hydroxide solution for 4.hours, then diluted with water (100 ml), and adjusted to pH 6 with 2N hydrochloric acid. After adding 3.34 g of gadolinium acetate, the aniXture is stirred for 16 hours at 50° C and the solution purified by way of ion exchangers, thus obtaining 3.90 g of the title compound as a white powder.
Analysis: C32H48Gd2N8014 (1083.28) C 35.48 H 4.47 Gd 29.03 N 10.34 (calc.) 35.31 4.18 28.81 10.57 (found) Example 10 Tris(Gadolinium) Complex of N6-Carboxymethyl-N3,N9-bis(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclo-dodecan-1-yl)carbonylmethyl-3,6,9-triazaundecanedioic Acid A suspension is prepared from 3.57 g of DTPA bis-anhydride in 100 ml of water and combined with 4.2 g of triethylamine and 8.61 g of N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane. The mixture is stirred at room temperature for 18 hours, combined thereafter with 200 ml of ethanol, and suctioned off from the precipitated solid matter. The filter cake is stirred with 100 ml of 1N
sodium hydroxide solution for:6 hours, then adjusted to pH 6 with 2N hydrochloric acid, 10.03 g of gadolinium acetate is added, and the mixture is stirred at 50° C for 18 hours. The solution is purified as 1341 1 ~s usual by way of ion exchangers, thus obtaining 8.32 g of the title compound as a colorless powder.
Analysis: C42H62Gd3N11020 (1512.77) C 33.35 H 4.13 Gd 31.18 N 10.18 (calc.) 33.41 4.05 31.02 10.03 (found) The preparation and isolation of complexing compounds will be demonstrated with the aid of the examples set forth below. The isolated complexing compounds can then be converted into the complexes, for example with various paramagnetic ions.
Example 11 N-(2-Hydroxyethyl)-1,4,7,10-tetraazacyclododecane-N' , N " , N " ' -triacetic Acid A solution of 6.46 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 150 ml of dichloromethane is combined with 3.2 g of triethylamine and 1.45 g of 2-chloroethanol. The mix-ture is agitated for 4 hours at room temperature, then shaken with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated under vacuum: The residue is stirred for 16 hours with 60 ml of 1N sodium hydroxide solution. By adding 5N hydrochloric acid, the pH is adjusted to 2.5.
The resultant suspension is poured on an ion ex-changer ("'DOWER"'~'S0W-X4 in the H+-form) , eluted with water and then with 0.5-molar NH3 solution, and concentrated under vacuum. The title compound is isolated by adding ethanol and suctioning off the precipitate. Yield: 4.24 g of the title compound;
purity is tested by pH titration and elementary analysis.
1341 1 ~fi Analysis: C16H30N407 (390.44) C 49.22 H 7.75 N 14.35 (calc.) 49.48 7.83 14.09 (found) Example 12 N-Methoxyacetyl-1,4,7,10-tetraazacyclododecane-N' , N " , N " ' -triacetic Acid A solution of 6.46 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 150 ml of dichloromethane is combined with 3.2 g of triethylamine and 1.79 g of methoxyacetic acid chloride.
After one hour, the mixture is shaken with soda solu-tion and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is stirred with 60 ml of 1 sodium hdyroxide solution for 5 hours at room temperature, then acidified to pH 2 by adding dilute hydrochloric acid, and the thus-obtained suspension is purified on a cation exchanger ("DOWER"
50 W-X4); elution is carried out with water and 0.5-molar NH3 solution. The eluate is concentrated and the title compound is precipitated by adding ethanol.
After suctioning and drying, 4.51 g of the title compound is obtained. Test for purity is done by titration and elementary analysis.
Analysis: C17H30N408 (418.45) C 48.80 H 7.23 N 13.39 (calc.) 48.98 7.41 13.18 (found) ~3~~ 1~s Example 13 N-[N-(2-Hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid A solution of 12.50 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid in 250 ml of dichloromethane is combined at 0° c with 5.22 g of triethylamine and then with 3.50 g of chloroformic acid isobutyl ester.
After one hour, 1.60 g of ethanolamine, dissolved in 50 ml of dichloromethane, is added dropwise, the mixture is stirred at room temperature for 2 hours, shaken with soda solution and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is chromatographed with chloroform/acetone (10:1) on 200 g of silica gel, thus obtaining 11 g of N-(2-hydroxyethyl)carbamoylmethyl-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane.
This product is stirred with 100 ml of 1N sodium hdyroxide solution for 5 hours at room temperature, then acidified with dilute hydrochloric acid to pH 2.5, and the suspension is purified on a cation exchanger ("DOWER" 50A-X4), elution being carried out with water and then with 0.5-molar NH3 solution. The eluate is extensively concentrated and, after addition of ethanol, the title compound is crystallized and isolated by filtration. Yield.
U~-~~-(U2-D2) _A1 s (I)~
U _0~_!U3_03)t_A2 wherein Y is a nitrogen or phosphorus atom, Al and A2, being identical or different, each mean a straight-chain or branched alkylene group of 2-6 carbon atoms, U1, U2, U3 and U4, being identical or different, each mean a direct bond or a straight-chain or branched alkylene group of 1-6 carbon atoms, Dl, D2, D3 and D4, being identical or different, respectively mean an oxygen or sulfur atom, an alkylene group of 1-6 carbon atoms, or a group N-R~
wherein R~ means a hydrogen atom, a straight-chain or branched alkylene chain of 1-4 carbon atoms carrying at the end a COOR1 group with R1 being a hydrogen atom or a metal ion equivalent, D5 has one of the meanings given for Dl, D2, D3 and D4 and can also mean i the group -CH- wherein R5 means a hydrogen atom or a straight-chain or branched, saturated or unsaturated Cl-C20-hydrocarbylene, e.g., alkylene group, optionally containing imino, phenylenoxy, phenylenimino, phenylene amide, an ester group and/or oxygen, sulfur and/or nitrogen, and/or optionally substituted by hydroxy, mercapto, epoxy, oxo, thioxm,imino and/or amino group(s), this alkylene group exhibiting at the end either a functional group or, linked via the latter, a macromolecule B, s and t mean integers from 0 to 5, RZ means hydrogen; a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acylalkylene group of 1-16 carbon atoms optionally substituted by one or several hydroxy or lower alkoxy groups; -CH2-X-V wherein X means carbonyl, a straight-chain or branched-chain alkylene group of 0-10 carbon atoms, optionally substituted by one or several hydroxy or lower alkoxy groups; or a straight-chain or branched-chain alkylene group of 5-23 carbon atoms, interrupted by oxygen atoms; but wherein formyl is not 1o substituted by hydroxy; V means N~R3 , or -COOR6 wherein ~Rq R3 and R9, independently of each other, mean hydrogen, a linear or branched alkyl group of 1-16 carbon atoms substituted, if desired, by one or several hydroxy or lower alkoxy groups, or R3 and R4 together with the nitrogen atom mean a five- or six-membered ring which is saturated and optionally contains a further hetero atom, and R6 means a saturated, unsaturated, straight-chain or branched-chain or cyclic hydrocarbon residue of up to 16 carbon atoms, or an 2o aryl or aralkyl group, or RZ or R3 mean a second macrocycle of Formula I', U~-0~-(UZ-~215-~~
lI~), which can be of a structure different from the basic skeleton of the first macrocycle, and which is linked by way of an alkylene chain containing 2-20 carbon atoms, 30 optionally carrying carbonyl groups at the ends and being interrupted, if desired, by one or several oxygen atoms or R1-carboxymethylimino groups or being substituted by one or several hydroxy, lower alkoxy or carboxy-lower alkyl groups, or RZ means B or CHZ-COB, with the provisos that, if RZ
stands for B or CHZ-COB, R5 is a hydrogen atom; that at least two COOR1 groups are present in the molecule; and that there are at least two hetero atoms in the macrocycle and that two hetero atoms of the macrocycle are linked to each other by way of an alkylene group with at least two carbon atoms; and 1o wherein functional groups present in the molecule are, if desired, conjugated with macromolecules and, if desired, free carboxy groups are used to form a salt with organic or inorganic bases or amino acids, and/or alkaline groups and are used to form a salt with inorganic or organic acids.
In particular, 1,4,7,10-tetraazacyclododecane derivatives of general Formula II are preferred R ~ 0 0 C--~~N/
(II), R ~ OOC-/N~/N~COOR ~
wherein:
each R1, independently of each other, is hydrogen or a metal ion equivalent of a complexible metal;
RZ is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, or -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is _N--""~R3 or -COOR6, wherein r.~ ~ ~~4 R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon to atoms, C6-io-aryl or C6-io-ar-C1_4-alkyl, or R2 or R3 represent a second macrocycle of Formula II', R ~ 0 0 C--~N~N~
(II~), R~OOC-/N~N~COOR2 which is of a structure the same as or different from that of the basic skeleton of Formula II, 20 linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or RZ is B or CHZ-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor, and functional groups present in the molecule are, if 3o desired, conjugated with biomolecules and optionally free carboxy groups are used to form a salt with organic or inorganic bases or amino acids, and alkaline groups are used to form a salt with organic or inorganic acids.
~' > , ~,:.3 1341 17fi _8_ The compounds of this invention and the solutions prepared therefrom fulfill the cited require-ments in a surprising way. They exhibit a high efficacy that can be adapted, by the choice of suitable metal atoms, to the respective principles of the diagnostic or therapeutic method (X-ray, NMR, ultrasonics, nuclear medicine).
The compounds of this invention are utilized, e.g., 1. For NMR diagnostics in the form of their complexes with the ions of the transition metals of atomic numbers 21-29, 42 and 44.
2. For NMR and X-ray diagnostics in the form of their complexes with the ions of the lanthanide elements of atomic numbers 57-70.
3. For ultrasonic diagnostics, those compounds can be employed which are useful in NMR
diagnostics, as well as those useful in X-ray diagnostics.
4. For radiodiagnostics and radiotherapy in '6 the form of their complexes with the radioisotopes of the elements of atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 62, 64, 70 or 77.
_ Q _ 1341 1 76 J
Even without specific measures, their pharma-cokinetics permit improvement in the diagnosis of numerous diseases. The complexes, for the largest part, are excreted unchanged and quickly so that especially when using relatively toxic metal ions as the active principle, no damaging effects that can be traced back to the metal are observed, in spite of a high dosage.
Practical usage of the novel complexes and complexing agents is also facilitated by their adequate, frequently even .very gobd~ :chemicalwstability.
Another essential advantage of the complexes and complexing agents described resides in their extra-ordinary chemical versatility. Besides by the choice of the central atom, the properties can be adapted by the choice of variegated substituents and/or salt-forming agents to the requirements regarding efficacy, pharmaco-kinetics, compatibility, ability to handle, etc.
Thus, it is possible to attain a specificity of the compounds, very desirable in diagnostics and therapy, for structures in the organism, for certain biochemical substances, for metabolic processes, for conditions prevailing in tissue or body fluids, especially by coupling to biological compounds or to compounds exhibiting interaction with biological systems.
Such compounds suitable for coupling can be of low molecular weight (for example, glucose, amino acids, fatty acids, bile acids, porphyrins) or high-molecular weight (polysaccharides, proteins, antibodies, etc.), or they can also represent structures foreign to the body but exhibiting a specific way of distribution in the body or reacting with components of the body.
. 1341 1 76 - to -Utilization of such principles will be possible the more easily, the more sensitive the detection method for a diagnostic agent, or the more effective a complex, being, for example, labeled radioactively, in therapy.
The compounds of this invention can also be used in radiotherapy in the form of their complexes with radioisotopes, e.g. 192Ir. The complex-forming agents of this invention are furthermore suited, as such or in the form of weak complexes with preferably endogenous ions (Ca2+, Mg2+, Zn2+~ ge2+/3+
for therapy of heavy metal poisoning or storage disea~~rs.
More generally, the compounds can be used in conjunction with any metal ion equivalent as long as the metal is chelatable (complexable) by a complexing agent.of this invention. Thus, the compounds, complexes and complex salts of this invention are also useful for the purposes known in the past for complexes of such metal ions.
Y preferably is N. Suitable alkylene groups throughout the foregoing depending on the number of C-atoms, include, e.g., straight-chained and branched methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, etc.
D's are preferably N-R~.
Compounds of general Formula I wherein R1 is hydrogen are denoted as complexing compounds, and those wherein at least two substituents R1 are metal ion equivalents are called metal complexes.
When R2 is hydrocarbyl, acyl or acylalkylene of 1-16 carbon atoms, this group can be linear or branched, saturated or unsaturated and can optionally be substituted by one or several hydroxy and/or lower alkoxy groups. Suitable lower alkoxy groups contain 1-4 carbon atoms and include, in particular, methoxy and ethoxy groups, but also n- or i-propoxy and n, i, or t-butoxy.
Suitable hydrocarbyl substituents for each of R2, R3, R4 and R6 as appropriate per above include saturated (alkyl), unsaturated (e. g., alkenyl) straight- or branched-chain or cyclic hydrocarbons of up to 16 carbon atoms, preferably saturated hydrocarbons which, in the case of R2, R3 and R4 are optionally substituted by 1-5 hydroxy and/or lower alkoxy groups.
Where the group is unsaturated, there typically are 1-3 unsaturated bonds. Examples of optionally substituted groups include methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 1-(hydroxymethyl)-ethyl, propyl, isopropenyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutenyl, 2-, 3- and 4-hydroxybutyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2- and 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, cyclohexyl and 2-methoxyethyl. "Acyl" typically is alkanoyl and benzoyl. Examples of optionally substituted acyl groups are the acetyl, methoxyacetyl, propionyl, 2-hydroxypropionyl, butyryl, 2,3-dihydroxybutyryl, benzoyl and valeryl groups: examples of optionally substituted acylalkylene groups include the phenacyl or p-phenylphenacyl groups, which can be, for example, alkyl (e.g. of 1-4 C-atoms)- or halogen (F, C1, Br, I)-substituted in the phenyl ring (e. g., 1-2 times), acetonyl, 2-oxobutyl, 2-oxopentyl, 2-oxohexyl, etc.
Preferred are hydrocarbyl and acyl groups of 1-7 carbon atoms and 1-4 hydroxy groups.
In X (as well as in R3 and/or R4) the number of the OH and/or lower alkoxy groups also is 1-5p the number of interrupting oxygen (oxa) atoms in X is typically 1-7 and, of course, the oxa atoms are non-adjacent.
R6 can also stand for C6-10 aryl or C6_10 ar-C1_4 alkyl, e.g., phenyl or benzyl.
Lower alkoxy groups throughout are to contain in each case 1-4 carbon atoms and encompass, e.g., in particular, methoxy and ethoxy groups but also propoxy and butoxy.
' ' 1341 176 - 12 a-Throughout, unsubstituted alkyl groups of 1-7 carbon atoms are preferred, such as, for example, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl groups. Furthermore preferred are mono- and polyhydroxy-substituted alkyl groups of 2-7 carbon atoms and 1-5, preferably 1-4 hydroxy groups, such as, for example, 2- and 3-hydroxypropyl, 1,3-dihydroxy-isopropyl, 1-(hydroxymethyl)ethyl, bis- and tris-(hydroxymethyl)methyl, 2,3-dihydroxy-1-hydroxymethyl-propyl, 2,3,4,5,6-pentahydroxyhexyl and, preferably, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 2,3-dihydroxypropyl, and 2,3,4-trihydroxybutyl.
Furthermore preferred are alkyl groups of 5-23 carbon atoms interrupted by oxygen atoms, e.g..2-[(,e~ -methoxy-, ethoxy- , mono-, di-, tri-, tetra-, penta-, hexa-(ethoxy)Jethyl or 3-[Cad-methoxy-, ethoxy-, mono-, ..., hexa(propoxy)Jpropyl.
When R3 and R4 represent jointly with the nitrogen atom a saturated five- or six=membered ring optionally containing a further hetero atom, e.g., N, O or S, preferably N or O, ~ R3 -N ~ R4 stands preferably for pyrrolidine, piperidine, morpholine or piperazine.
In case R~ stands for a straight-chain or branched alkylene chain containing a COOR1 group at the end, such chain comprises 1-4 carbon atoms; the methylene group is preferred.
The alkylene chain (K) to which the second macrocycle I' is linked carries at the ends optionally carbonyl groups (-CO-K-CO-) and contains 2-20 carbon atoms. This chain can be interrupted by one or several (e. g., 1-7) oxygen atoms) and/or carboxymethylimino 13 41 i groups) and can be substituted by one or several (e. g., 1-5) hydroxy, lower alkoxy and/or carboxy-lower alkyl group(s). Lower alkoxy and lower alkyl groups are to contain respectively 1-4 carbon atoms and comprise, in particular, methoxy, ethoxy, methyl and ethyl groups.
K is a straight- or branched-chain alkylene group interrupted, if desired, by one or several oxygen atoms and/or carboxymethylimino groups, and optionally substituted as described, can contain 2-20 carbon atoms and optionally 2-4 oxa atoms and/or 1-3 carboxymethyliminogroups. Furthermore, the alkylene chain K can be substituted by 1-5 hydroxy, alkoxy or carboxy-lower alkyl groups.
Examples of K are:
-(CH -CH -0-CH -CH )-, -(CH -0-CH ) -, -(CH2)2-, -CHZ-0-CH2-, -(CH2)4-. 2 2 2 2 2 2 2 -CH -CH -(0-CH -CH ) -, -CH -CH -(0-CH -CH ) -, -(CHZ-0-CH2)3-. 2 2 2 2 3 2 2 2 2 4 -CH2 CH-.
OH
-~H-~H-, -CH2-i-, -CH2-~H-iH-CHZ.
~H2 ~H2 ~H2 COOH COOH COOH
. 1341 1 76 The alkylene group contained in R5 can be straight-chain, branched, cyclic, aliphatic, aromatic or arylaliphatic and can contain up to 20 carbon atoms, Straight-chain mono- to hexamethylene groups are preferred, as well as C1-C4-alkylenephenylene groups.
If the alkylene group contains a phenylenoxy group then the latter is preferably linked in the p-position via a methylene group to the -CH-group of the basic skeleton of the compound of general Formula I. The mentioned aromatic nature of an R5 alkylene group will be derived from the mentioned phenylenoxy, phenylene, and/or phenylenimino groups. Typically, the R5 chain can contain up to 4 of the mentioned interrupting groups, e.g., oxa, phenylenoxy, etc.., and 1-5 of the mentioned substituents.
Preferred functional groups present at the end of the R5-alkylene group are, for example, the benzyl ester, ethyl ester, tert-butyl ester, amino, C1-C6-alkylamino, aminocarbonyl, hydrazine, hydrazino-carbonyl, maleimido, methacrylamido, methacryloyl-hydrazinocarbonyl, maleimidamidocarbonyl, halo, mercapto, hydrazinotrimethylenehydrazinocarbonyl, aminodimethyl-eneamidocarbonyl, bromocarbonyl, phenylenediazonium, isothiocyanate, semicarbazide, or thiosemicarbazide group.
For explanatory purposes, several selected R5 substituents will be set forth below:
0y _CH2_C6H4-0(CH2)3-N ~ ~ -CH2-C6H4-0(CH213NH~C
I
-CHZ-CSH;-0-CHZ-C02GH2C6H~, -CHZ-CSN4-0(CH2)5COZCH2CSFi5, 0 -CHZ-C6H~-0(CH2)SCONHNH2, -CH2-C6H4-CONHNH~ , -C~z-C6H4-0(CH2)4-SH, N -C H -0(CH 1 NHNH , -CH2-CSH4-OlCH2)5-CO~IH-N ~ , -CHZ-C6H4-0(CNZ)38r, -CH2-CSH4-0(CHZ)SCONHNH-(CH2)3-NHNH2, -CH2-NHNHZ, -CHZ-SH, -CH2CONHNH2, -(CH2)3SH, -CHZ-C6H4-0-CH2COBr, -CSH4NHCOCH28r, II -CH -C H -NN , -C H -N , -C H NHCS, -CH2-C6H4-OCH2-C-NH-(CHZ)ZNH2, 2 6 4 2 6 4 2 6 4 II CH ) -S-SJ ~ ~I , -NHCO-NH-NH2, -NHCS-NH-NHZ, -CH2-C6H4-NH-C-( 2 2 ~D~ II
-CH -C H -0-CH2-Ct!-CH2, -CHZ-C6H4-0-CH2-IC-NH-(CH21~0-C-NHNH2, -CH -C6H;-0-CH2-CHOH-CHZ-NH(CH2))0-IC-NHNH2, -OCH2-C-N-CH2-(CHOH)4-CHZOH, -CH2-CH-CH2, -CH2-0-(CHZ)3-N ~, -CH2-0-(CH2)~-SH, I
-CH2-D-(CHZ)3-NHNHZ, -CHZ-0-CHZ-IC-NH-NHZ, -CHZ-0-CH2-CH2-NHZ, H -0-CH -NH-IC-(CH ) -S-S~~N~I , CN -0-CHZ-IC-NH-(CH2)~0-IC-NH-NH2, ,z;
".~i - 16 -., If not all acidic hydrogen atoms are sub-stituted by the central ion, then one, several or all remaining hydrogen atoms) can be replaced by cations of inorganic and/or organic bases or amino acids.
Suitable inorganic cations are, for example, the .s lithium ion, the potassium ion, the calcium ion and, in particular, the sodium ion. Suitable cations of organic bases are, inter alia, those of primary, secondary or tertiary amines, e.g. ethanolamine, di-ethanolamine, morpholine, glucamine, N,N-dimethyl-' glucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of , lysine, of arginine and of ornithine.
The complex compounds can also be linked to macromolecules, preferably to one known to be partic-ularly .accumulated in the organ or organ part to be investigated. Such macromolecules include, fo r example, hormones, dextrans, polysaccharides, polychelones, hydroxyethyl starch, polyethylene glycol, desferriox-amines, bleomycins, insulin, prostaglandins, steroid hormones, amino sugars, amino acids, peptides, such as polylysine, proteins (such as, for example, immuno-globulins and monoclonal antibodies) or lipids (also in the form of liposomes). Conjugates with albumins deserve special mention, such as human serum albumin, with antibodies, such as, for example, monoclonal antibodies specific for tumor-associated antigens or antimyosin.
Instead of the biomolecules; it is also possible to link suitable synthetic polymers, such as poly-ethylenimines. The diagnostic media formed there-from are suited, for example,'for use in tumor and infarction diagnostics. Especially suitable monoclonal antibodies for conjugation are those directed against predominantly cell-membrane-fixed antigens.
Suitable as such antibodies are, for example, monoclonal antibodies and/or their fragments [F(ab)2]
for tumor imaging, directed, for example, against the carcinoembryonal antigen (CEA), human chorionic gonadotropin (S-hCG), or other tumor-fixed antigens, such as glucoproteins. Also suitable, inter alia, are anti-myosin, anti-insulin and anti-fibrin antibodies.
Suitable for liver tests and/or for tumor diagnostics are, for example, conjugates or clathrates with liposomes (used, for instance, as uni-laminar or multilaminar phosphatidylcholine-cholesterol vesicles).
All of these conjugations to macrobio-molecules can be effected fully conventionally.
' 1341 1 76 ._ - is -The macrocyclic compounds of general Formula I are produced in that, in a manner known per se, in compounds of general Formula III
/U~-D1.-IUZ-D2.)S-AI
D5 ~y_R2~ tIII)~
\U;-D4.-(U3-D3.)t-A
wherein Y, A1, A~, Ul, U2, U3, U4, s and t have the meanings given above, D1 , D2 , D3 and D4 have the same meanings as Dl, D2, D3 and D4 but contain, in place of the COORl group, the COOZ group wherein Z means a carboxy blocking group, has the meanings given for D1~, D2~, D3~ and D4~, , and also represents the group R5 -~H-wherein R5 means R5, but without exhibiting a macromolecule B, and R2 has the meanings given for R2, but is not to stand for a macromolecule B or the group CH2-COB, the blocking groups Z are split off and the resultant acids (Rl of general Formula I means hydrogen), if desired (a) are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and subsequently, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids;
or (b) are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and subsequently the thus-obtained metal complexes, in a manner known per se, are linked by way of functional groups contained in the molecule, or by way of R2 or, respectively, by way of the CO-group contained in R' 'to a macrocycle , and, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids;.
or ._ a_.. .~o.;~;.~.«; t. . ~ ~,... . ~. .
(c) are conventionally linked by way of the functional groups contained in the molecule, or by way of R2 or, respectively, by way of the CO-group contained in R2 to a macrocycle /and subsequently are conventionally reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 and thereafter, if desired, any present acidic hydrogen atoms are converted into physiologically compatible salts with inorganic and/or organic bases or amino acids, and any present alkaline groups are converted into physiologically compatible salts with inorganic or organic acids.
Carboxy blocking groups Z that can be used are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)methyl group, as well as trialkylsilyl groups.
Cleavage of the blocking groups Z takes place in a manner known per se, for example by hydrolysis, alkaline saponification of the esters, preferably with an alkali in an aqueous-alcoholic solution at temperatures of 0° to 50° C or, in case of, for example, tert-butyl esters, with the aid of trifluoroacetic acid.
The educts are prepared by cyclizing of two 5"
reactants, one of which is R -substituted, wherein 5" 5' R stands for a substituent convertible into R ;
the thus-obtained cyclic compounds are subsequently reacted, optionally after splitting off blocking groups, with halogen alkanes, halogen esters, halogen acids, halogen ketones, acyl halogenides or acyl anhydrides in order to introduce. the substituent R2.
The cyclization is performed according to methods known in the literature (for example, Org.
Synth. 58 . 86 [1978], Macrocyclic Polyether Syntheses, Springer Publishers, Berlin, Heidelberg,New York, 1982, Coord. Chem. Rev. 3 . 3 [1968], Ann. Chem. 1976 . 916):
one of the two reactants carries at the end of the chain two fugitive groups, the other carries two nucleophiles displacing these fugitive groups.
An example that can be cited is the reaction of end-positioned dibromo-, dimesyloXy-, ditosyloxy- or dialkoxycarbonylalkylene compounds optionally con-taining hetero atoms with end-positioned diaza-alkylene compounds optionally containing additional hetero atoms in the alkylene chain, of which 5"
one of the two reactants is R -substituted.
Nitrogen atoms present are optionally blocked, for example in the form of tosylates, and are liberated _ 22 _ prior to the subsequent alkylation reaction in accordance with methods known from the literature.
If diesters are used in the cyclization reaction, the thus-obtained diketo compounds must be reduced by methods known to those skilled in the art, for example with diborane.
The subsequent alkylation takes place with halogen ketones, halogen esters, halogen acids or halogen alkanes which can be substituted by one or several hydroxy or lower alkoxy groups and may contain oxygen atoms) in the chain. Furthermore, the alkyl residue can also contain an end-positioned amino group.
If alkylation takes place with a dihalogenated alkane, compounds of general Formula III are produced having two macrocyclic rings joined by way of a carbon bridge.
Additional methods known from the literature for the synthesis of compounds having more than one ring are, for example, reactions of an amine with a carbonyl compound (e. g. the acid chloride, mixed anhydride, activated ester, aldehyde); of two amine-substituted rings with a dicarbonyl compound (e. g.
oxalyl chloride, glutaric dialdehyde~; of two rings each exhibiting a nucleophilic group with an alkylene com-pound carrying two fugitive groups; in case of terminal acetyls, oxidative coupling (Cadiot, Chodkiewicz in Viehe "Acetylenes", 597-647, Marcel Dekker, New York, 1969). The, chain linking the rings can subsequently be modified by secondary reactions (e. g.
hydrogenation).
The saponification of the ester groups obtained during alkylation with halogen esters, which may be necessary, is performed according to methods known to those skilled in the art (for example with ' ' 1341 176 ' alkaline catalysts, such as alkali or alkaline earth carbonates or hydroxides).
In the alkylation with haloacetic acid, an intermediate product is obtained wherein R2 -CH2X-COON; this product is converted into the monoamide by way of the mixed anhydride with chloroformic acid ester or.with the aid of dicyclohexylcarbodiimide and reaction with a primary or secondary amine of the general formula ~ R3 .
~ R
Examples for suitable amines are: dimethyl-amine, diethylamine, di-n-propylamine, diisopropyl-amine, di-n-butylamine, diisobutylamine, di-sec-butylamine, N-methyl-n-propylamine, dioctylamine, dicyclohexylamine, N-ethylcyclohexylamine, diisopropenyl-amine, benzylamine, aniline, 4-methoxyaniline, 4-dimethylaminoaniline, 3,5-dimethoxyaniline, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethyl-piperazine, N-(2-hydroxyethyl)piperazine, N-(hydroxy-methyl)piperazine, piperazinoacetic acid isopropylamide, N-(piperazinomethylcarbonyl)morpholine, N-(piperazino-methylcarbonyl)pyrrolidine, 2-(2-hydroxymethyl)-piperidine, 4-(2-hydroxyethyl)piperidine, 2-hydroxy-methylpiperidine, 4-hydroxymethylpiperidine, 2-hydroxy-methylpyrrolidine, 3-hydroxypiperidine, 4-hydroxy-piperidine, 3-hydroxypyrrolidine, 4-piperidone, 3-pyrroline, piperidine-3-carboxylic acid amide, piper-idi.ne-4-carboxylic acid amide, piperidine-3-carboxylic acid diethylamide, piperidine-4-carboxylic acid di-methylamide, 2,6-dimethylpiperidine, 2,6-dimethyl-morpholine, N-acetylpiperazine, N-(2-hydroxypropionyl)-piperazine, N-(3-hydroxypropionyl)piperazine, N-(methoxyacetyl)piperazine, 4-(N-acetyl-N-methylamino)-piperidine, piperidine-4-carboxylic acid (3-oxapentamethylene)amide, piperidine-3-carboxylic acid (3-oxapentamethylene)amide, N-(N',N'-dimethyl-carbamoyl)piperazine, pyrazoline, pyrazolidine, imid-azoline, oxazolidine, thiazolidine, 2,3-dihydroxypropyl-amine, N-methyl-2,3-dihydroxypropylamine, 2-hydroxy-1-(hydroxymethyl)ethylamine, N,N-bis(2-hydroxyethyl)amine, N-methyl-2,3,4,5,6-pentahydroxyhexylamine, 6-amino-2,2-dimethyl-1,3-dioxepin-5-ol, 2-hydroxyethylamine, 2-amino-1,3-propanediol, diethanolamine, ethanolamine.
The polyhydroxyalkylamines can advantageously be used for the reaction also in the blocked form, for ex=
ample as O-acyl derivatives or as ketals. This is applicable especially if these derivatives can be pro-duced more conveniently and cheaply than the poly-hydroxyalkylamines proper. A typical example is 2-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol, the acetonide of 1-amino-2,3,4-trihydroxybuta~e, produced in accordance with DOS 31 50 917 published June 30, 1983.
The subsequent removal of the blocking groups does not entail any problems and can take place, for example, by treatment with an acidic ion exchanger in an aqueous-alcoholic solution.
Acylation is performed with a corresponding acyl derivative, especially with an acyl halogenide or anhydride. When using anhydrides or halogenides of di-or polycarboxylic acids, then compounds of general Formula III are obtained wherein the two macrocyclic rings are linked in the manner of an amide by way of a carbon bridge.
Suitable as substituents RS~~ convertible into the substituents R5 exhibiting at the end a functional group suited for linkage to a macromolecule are, inter alia, hydroxy and nitrobenzyl, hydroxy and carboxy-alkyl, as well as thioalkyl residues of up to 10 carbon ~~ ~ ,s..J .
atoms. They are converted in accordance with methods disclosed in the literature and known to those skilled in the art CChem. Pharm. Bull. 33 . 674 [1985], Compendium of Org. Synthesis vol. 1-5, Wiley and Sons, Inc.) into the desired substituents (e.g. with the amino, hydrazino, hydrazinocarbonyl, methacryloyl-hydrazinocarbonyl, maleimidamidocarbonyl, halogeno, halogenocarbonyl, mercapto group as the functional group); in case of the nitrobenzyl residue, a catalytic hydrogenation (e. g. according to P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press 1967) must first be performed to obtain the aminobenzyl derivative.
Examples for the conversion of hydroxy or amino groups bound to aromatic or aliphatic residues are the reactions performed in anhydrous, aprotic solvents, such as tetrahydrofuran, dimethoxyethane or dimethyl sulf-oxide in the presence of an acid captor, such as, for example, sodium hydroxide, sodium hydride or alkali or alkaline earth carbonates, e.g. sodium, magnesium, potassium, calcium carbonate, at temperatures of between 0° C and the boiling point of the respective solvent, but preferably between 20° C and 60° C, with a substrate of general Formula IV
W-L-Fu (IV) wherein W is a nucleofugic entity, such as, for ex-ample, C1, Br, I, CH3C6H4S03 or CF3S03; L is an aliphatic, aromatic, arylaliphatic, branched, straight-chain or cyclic hydrocarbon residue of up to 20 carbon atoms; and Fu is the desired end-positioned functional group.
' 1341 1 76 Examples of compounds of general Formula IV
are Br(CH2)2NH2, 8r(CHZ)30H, BrCH2C00CH3, BrCH2C02tBu, Br(CH2)4C02C2H5, BrCH20COBr, 8rCH2CONH2, C1CH2COOC2H5, BrCH2CONHNH2, BrCH2-CH-CH2, CF3S03(CHZ)3Br, 8rCH2C=CH, BrCH2CH=CH2.
Conversions of carboxy groups can be conducted, for example, according to the carbodiimide method (Fieser, Reagents for Organic Syntheses 10, 142) via a mixed anhydride (Org. Prep. Proc. Int. 7 . 215 [1975]) or via an activated ester (Adv. Org. Chem. Part B, 472).
The compounds of general Formula I wherein Rl is a hydrogen atom represent complex-forming com-pounds. They can be isolated and purified or, without isolation, can be converted into metal complexes of general Formula I wherein at least two of the substi-tuents Rl mean a metal ion equivalent.
The metal complexes of this invention are prepared as disclosed in the references cited above by dissolving or suspending the metal oxide or a metal salt (e. g. the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-29, 31, 32, 38, 39, 42-44, 49, 57-70 or 77 in water and/or a lower alcohol (such as methanol, ethanol or iso-propanol) and reacting with a solution or suspension of the equivalent amount of the complex-forming acid of general Formula I wherein Rl means a hydrogen atom, and subsequently, if desired,'substituting any present acidic hydrogen atoms of acid groups by cations of inorganic and/or organic bases or amino acids.
Neutralization takes place in this process with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium or lithium and/or with the aid of organic bases, such as, _ 1341 176 inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as alkaline amino acids, such as, for example, lysine, arginine and ornithine.
In order to prepare the neutral complex compounds, it is possible, for example, to add to the acidic complex salts, in an aqueous solution or sus-pension, such an amount of the desired bases that the neutral point is reached. The resultant solution can then be concentrated to dryness under vacuum. It is frequently advantageous to precipitate the thus-formed neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others) and thus to obtain crystallized products which can be readily isolated and easily purified. It proved to be particularly advantageous to add the desired base to the reaction mixture as early as during the complex formation and thereby to save a process step.
If the acidic complex compounds contain several free acidic groups, it is often advantageous to prepare neutral mixed salts containing inorganic as well as organic cations as counterions.
This can be done, for example, by reacting the complex-forming acid in an aqueous suspension or solution with the oxide or salt of the element yielding the central ion and half the amount,required for neutralization,of an organic base; isolating the thus-formed complex salt; purifying same if desired; and then combining same, for complete neutralization, with the needed amount of inorganic base. The sequence of adding the bases can also be reversed.
1341 1 7fi ' Alkaline groups can be converted into pharmaceutically compatible salts with inorganic and/or organic acids.
Examples for suitable inorganic bases are lithium, sodium and potassium hydroxide. Organic bases are, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as alkaline amino acids, such as, for example, lysine, arginine and ornithine.
Inorganic acids, e.g, hydrochloric acid, and organic acids, e.g. citric acid, can be used for forming the salt with alkaline groups.
Conjugate formation can be effected, for ex-ample, by way of a carboxy group of the complex compound or by way of the functional group, as defined hereinabove, present at the end of the C1-C20-alkylene group of sub-stituent R5. When forming the conjugate of acids with macromolecules, several acid residues can be bound to the latter. In this case, several central ions can be bound to a macromolecule.
Coupling to the desired macromolecules like-wise takes place according to conventional methods as disclosed, for example, in Rev. Roum. Morphol. Embryol.
Physiol., Physiologie 1981, 18 . 241 and J. Pharm. Sci.
68 . 79 (1979), for example by reacting the nucleophilic group of a macromolecule, such as the amino, phenol, sulfhydryl, aldehyde or imidazole group, with an activated derivative of the complexing compound. Ex-amples of activated derivatives are monoanhydrides, acid chlorides, acid hydrazides, mixed anhydrides (see, for example, G.E. Krejcarek and K.L. Tucker, Biochem.
Biophys. Res. Commun. 1977, 581), activated esters, nitrenes or isothiocyanates. Conversely, it is also possible to react an activated macromolecule with the .... ..r~W .~... ~.~~*...., ..*,~,..,.. .*_..., . *. *....*.... ....:.... a ..
. . ..
- 1341 17fi complex-forming acid. For conjugation with proteins, also suitable are substituents having, for example, the structure C6H4,N2, C6H4NHCOCH2, C6H4NHCS, or C6H40CH2C0.
Conjugation of the complex-forming acid with dextrans and dextrins also takes place in accordance with conventional methods, e.g. by activation of the polysaccharides with cyanogen bromide and subsequent reaction with amino groups of the complex-forming acid.
When using complex compounds which contain radioisotopes, they can be prepared according to the methods described in "Radiotracers for Medical Applica-tions", vol. 1, CRC-Press, Boca Raton, Florida.
All starting materials used in the mentioned conventional reaction are known or conventionally preparable from known starting materials.
The pharmaceutical agents of this invention are likewise prepared conventionally by suspending or dissolving the complex compounds of this invention --optionally while combining them with the additives customary in galenic pharmacy -- in an aqueous medium and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as, for ex-ample, tromethamine), small amounts of complexing agents (such as, for example, diethylenetriaminepenta-acid acid) or, if required, electrolytes, e.g. sodium chloride or, if needed, antioxidants, such as, for example, ascorbic acid.
If suspensions or solutions of the agents of this invention in water or physiological saline solution are desirable for enteral administration or other pur-poses, then they are mixed with one or several of the auxiliary agents customary in galenic pharmacy (for example, methylcellulose, lactose, mannitol) and/or tensides (for example lecithins, and those sold under the trademarks "Tween", "Myrj") and/or flavoring materials) to improve taste (e. g. ethereal oils).
_;
.._.~..,..a.,'~~~!Y!0.::-.~.::~~~.: ~..~NIGn~S:v,.... ...... ..
' ' 1341 176 In principle, it is also possible to prepare the pharmaceutical agents of this invention even without isolating the complex salts. In any event, special care must be directed toward effecting chelate forma-tion in such a way that the salts and salt solutions according to the invention are practically devoid of uncomplexed, toxically active metal ions.
This can be ensured, for example, with the aid of dye indicators, such as xylenol orange, by control titrations during the manufacturing process. Therefore, the invention also relates to processes for the produc-tion of the complex compounds and their salts. Purifica-tion of the isolated complex salt remains as a final safety measure.
The pharmaceutical agents of this invention preferably contain 1 umol to 1 mol per liter of the complex salt and are normally administered in doses amounting to 0.001 - 5 mmol/kg. They are intended for entral and parenteral administration.
The agents of this invention fulfill the variegated requirements for suitability as contrast media for nuclear spin tomography. Thus, they are excellently suited for improving the information content of the image obtained with the aid of the nuclear spin tomograph upon oral or parenteral administration, by increasing the signal intensity. Furthermore, they exhibit the high efficacy necessary to introduce into the body a minimum amount of burdening foreign substances, and they show the good compatibility necessary for main-taining the noninvasive character of the examinations.
The good water solubility of the agents of this invention makes it possible to prepare highly concentrated solutions, thus maintaining the volume load on the circulation within tolerable limits and compensating for dilution by body fluids. Furthermore, the agents of the present invention not only exhibit high stability in vitro, but also a surprisingly high stability in vivo, so that a release or exchange of the ions -- toxic per se -- which are not bound in a co-y valent fashion in the complexes takes place only extreme-ly gradually within the time period during which the novel contrast media are again completely eliminated.
In general, the agents of this invention are dosed, for use as NMR diagnostics, in quantities of 0.001 - 5 mmol/kg, preferably 0.005 - 0.5 mmol/kg.
Details of usage are discussed, fox example, in H.J. Weinmann et al., Am. J. of Roentgenology 142 . 619 (1984), e.g., analogously to Gd-DTPA.
Extremely low doses (below 1 mg/kg) of organ-specific NMR diagnostics are .usable,: for example, for the detection of tumors and of cardiac infarctions. Fur-thermore, the complex compounds of this invention can be utilized advantageously as shift reagents.
On account of their favorable radioactive properties and the good stability of the complex com-pounds contained therein, the agents of this invention are also suitable as radiodiagnostic media. Details of their use and dosage are described, for example, in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.
Another imaging method with radioisotopes is positron emission tomography, utilizing positron-emitting isotopes, such as, for example, 43Sc, 44Sc, 52Fe, 55Co and 68Ga. (Heiss, W.D., Phelps, M.E., "Positron Emission Tomography of Brain", Springer Publishers, Berlin, Heidelberg, New York, 1983.) The compounds of this invention can also be used in radioimmunotherapy. This procedure differs from the corresponding diagnostics only by the amount and type of radioactive isotope employed. The objective herein is destruction of tumor cells by high-energy shortwave radiation with as short a range as possible.
The specificity of the antibody employed is herein of decisive importance since unspecifically localized anti-body conjugates lead to destruction of healthy. tissue.
The antibody or the antibody fragment of the antibody metal complex of this invention serves for transporting the complex,in an immune-specific way for the respective antigen, to the target organ where the metal ion selected on account of its cytocidal proper-ties can emit radiation causing lethal damage to the cells. Suitable S-emitting ions are, for example, 46Sc~ 47Sc, 48Sc, ~2Ga and ~3Ga. Suitable a-emitting ions exhibiting low.~half-life values are, for example, 211Bi~ 212Bi~ 213Bi and 214Bi,- wherein 212Bi is preferred.
In the in vivo administration of the therapeutic agents of this invention, these agents can be given together with a suitable excipient, e.g. serum or physiological sodium chloride solution and together with another protein, such as, for example, human serum albumin. The dose in this connection is dependent on the type of cellular disorder, the metal ion used, and the type of imaging method.
The therapeutic media of this invention are administered parenterally, preferably intravenously.
See, e.g., R.W. Kozak et al, Trends in Biotechnology (TIBTEC), October 1986, 262.
The agents of this invention are excellently suited as X-ray contrast media; in this connection, it should be emphasized, in particualr, that their use does not bring about any indications of anaphylaxis-type reactions in biochemical-pharmacological tests. They are especially valuable for digital subtraction techniques on account of their favorable absorption properties in regions of higher tube voltages.
In general, the agents of this invention are used, when administered as X-ray contrast media, in doses analogous to, for example, meglumine diatrizoate in amounts of 0.1 - 5 mmol/kg, preferably 0.25 - 1 mmol/kg.
Details of usage of X-ray contrast media are discussed, for example, in Barke, "Roentgenkontrastmittel"
[X-Ray Contrast Media], G. Thieme, Leipzig(1970),and P. Thurn, E. Btlcheler, "Einfuehrung in die Roentgen-diagnostik" [Introduction to X-Ray Diagnostics], G. Thieme, Stuttgart, New York(1977).
The agents according to the invention are also 20. suitable -- since their acoustic impedance is higher than that of body fluids and tissues -- as contrast media for ultrasonic diagnostics, especially in the form of suspensions. They are generally used in doses amounting to 0.1 - 5 mmol/kg, preferably 0.25 - 1 mmol/kg.
Details of the use-of ultrasonic diagnostica are disclosed, for example, in T.B. Tyler et al., Ultrasonic Imaging 3.323 (1981), J.I. Haft, "Clinical Echocardiography", Futura, Mount Kisco, New York 1978, and G. Stefan, "Echokardiographie" G. Thieme, Stuttgart/
New York, 1981.
In summation, novel complex-forming compounds, metal complexes, and metal complex salts are provided, opening up new possibilities in diagnostic and therapeutic medicine. This development appears to be valuable, above all, in connection with the evolution of novel imaging methods in medical diagnostics.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
.4 The synthesis of starting materials will be described below by way of example, beginning with a cyclization reaction:
(a) 1-Benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane At 100° C under agitation, 145 g of N,N-bis[2,2'-(p-tolylsulfonyloxy)]ethanebenzylamine, dissolved in 900 ml of dimethylformamide is added dropwise within 3 hours to a solution of. 164.6 g o.f N,N' ,N' '-tris (p-tolyl-sulfonyl)diethylenetriamine-N,N " -disodium salt in 2.16 1 of dimethylformamide. Then, under agitation at 80° C, one liter of water is added dropwise, and the mixture is further stirred for 18 hours at room tempera-ture, whereafter it is cooled to 0° C and the precip-itate is suctioned off, washed with a small amount of ice-cold ethanol and dried at 15 torr and 60° C, yielding 175 g of the title compound.
Alternative Route 1 An analogous method for preparing tetraazacyclo-dodecane derivatives is found in M. Hediger and T.A.
Kaden, Helv. Chim. Acta 66 . 861 (1983).
At 80-85° C, 30.94 g of N,N',N " -tris(p-tolyl-sulfonyl)diethylenetriamine-N,N " -disodium salt and 28.12 g of N-bis(2-methanesulfonyloxyethyl)triphenyl-methylamine are stirred with 530 ml of dimethylformamide for 20 hours, then cooled off and stirred into a solu-tion of 30 g of potassium carbonate in 5 1 of ice water.
The precipitate is suctioned off, the filter cake is washed with 0.5 1 of water, and dried at 20oC under vacuum at 150 torr. For purification, the product is dissolved in 230 ml of chloroform and 5 ml of triethylamine, filtered, concentrated to 200 ml under vacuum, and 1341 1 7fi the solution is combined under boiling heat with 250 ml of ethyl acetate. The mixture is allowed to cool off overnight and the thus-precipitated crystals are suctioned off, yielding 22.18 g of 1,4,7-tris(p-tolylsulfonyl)-10-triphenylmethyl-1,4,7,10-tetraazacyclododecane, mp 185-188 C (decomposition).
In order to split off the trityl blocking group, 31.4 g of the tritosyl-trityl derivative pr-epared in this way is stirred in a mixture of 100 ml of glacial acetic acid, 75 ml of water, and 300 ml of dioxane for one hour at 80 C. Then the mixture is exhaustively concentrated~under vacuum at 60,C, diluted with 300 ml of ice water and combined with 40 ml of 11N sodium hydroxide solution (pH above 12). This mixture is shaken with 300 ml of chloroform, the phases are separated, the aqueous phase is extracted twice with respectively 100 ml of chloroform, and the combined ~,t, chloroform phases are dried over sodium sulfate and evaporated under vacuum. The frothy residue is treated with 300 ml of diethyl ether, thus bringing about.
crystallization. The mixture is suctioned off, the crystals~are dried under vacuum at 60 C and 150 torr, and the yield is 21 g of 1,4,7-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane, mp 202-203 C.
The thus-obtained tritosyl compound (21 g) is dissolved in 200 ml of dimethylformamide, the solution is combined in succession with 13.71 g of anhydrous potassium carbonate, 4.95 g of sodium iodide, and 7.92 g of benzyl bromide, and agitated for.5 hours at 100 C, then cooled to 20 C, and the mixture is stirred into 4 1 of ice water, suctioned off, and the residue dissolved in 2 1 of dichloromethane. The solution is extracted with 100 ml of water, dried over sodium sulfate and evaporated under vacuum.
' 1341 1 76 The residue is dissolved under boiling heat in 500 ml of acetonitrile, allowed to crystallize over-night, suctioned off, and the crystals are dried at 50° C and 150 torr, yielding 16.20 g of 1-benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraaza-cyclododecane, mp 217-219° C.
(b) N-Benzyl-1,4,7,10-tetraazacyclododecane 150 g of 1-benzyl-4,7,10-tris(p-tolylsulfonyl)-1,4,7,10-tetraazacyclododecane is heated with 900 ml of HBr/acetic acid (40$ strength) and 125 g of phenol for 16 hours to 50° C. After cooling to 20° C, the mixture is diluted with one liter of ether, cooled to -5° C, and the thus-precipitated crystals are suctioned off.
In order to isolate the free base, the product is dis-solved in 500 ml of 4N sodium hydroxide solution, saturated with potassium carbonate, and repeatedly ii!
extracted with chloroform, dried over magnesium sulfate, and evaporated under vacuum. Yield: 39 g of the title compound as a light-yellow, viscous oil. A sample was characterized as the trihydrochloride: mp 210° C
(under decomposition).
Alternative Route 2 A solution of 11.2 g of 1,4,7,10-tetraazacyclo dodecane in 900 ml of tetrahydrofuran is combined at -20° C with 58 ml of triethylamine and, under agita tion, a solution of 16.2 ml o,f benzoyl chloride in 280 ml of tetrahydrofuran is added dropwise thereto within 3 hours. During this step, the room temperature rises to slightly above -10° C.
The mixture is then agitated for 16 hours at 0-10° C, the precipitate is filtered off, and the solution is evaporated under vacuum. The residue is chromato-graphed on 1 kg of silica gel and eluted with a ' - 1341 1 7~
solution of dioxane-water-ammonia (8:1:1). The fractions uniform in accordance with TLC are combined, evaporated, dissolved in dichloromethane, and filtered to eliminate a slight turbidity, and the solution is evaporated, thus obtaining 19.60 g of 1,4,7-tribenzoyl-1,4,7,10-tetraazacyclododecane, mp 120-125 C.
11.5 g of the thus-obtained tribenzoate is stirred in 150 ml of dimethylformamide with 8.3 g of anhydrous potassium carbonate, 3.0 g of sodium iodide, and 7.2 ml of benzyl bromide for 18 hours at 100 C.
The mxiture is then filtered, the solution evaporated under vacuum, the residue stirred twice with respectively 50 ml of hexane, and decanted. The hexane phases are discarded. For purification, the product is dissolved in dichloromethane and chromatographed with dichloro-methane-methanol (37:3) over 0.5 kg of silica gel, thus obtaining 10.2 g of 1,4,7-tribenzoyl-10-benzyl-1,4,7,10-tetraazacyclododecane, mp 105-109 C.
In order to split off the benzoyl groups, this product (2.87 g) is dissolved in 290 ml of tetrahydro-furan, combined with 11.2 g of potassium tert-butylate, and heated under reflux for 48 hours. The mixture is filtered, evaporated under vacuum, the residue combined under ice cooling with 100 ml of water and extracted three times with respectively 50 ml of dichloromethane.
The combined dichloromethane phases are shaken with 10 ml of water, dried over sodium sulfate, and evaporated under vacuum. The initially oily residue crystallizes very gradually and is triturated with 20 ml of hexane.
After suctioning off and drying, 1.15 g of N-benzyl-1,4,7,10-tetraazacyclododecane is obtained, mp 75-78 C.
1341 1 7~
(c) 1-Benzyl-4,7,10-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane At 0° C, a solution of 131.8 g of N-benzyl-1,4,7,10-tetraazacyclododecane in 1.5 1 of dichloro-methane is combined in succession with 200 g of triethylamine and, within 2 hours, with 260 g of bromoacetic acid ethyl ester. The mixture is stirred for 16 hours at room temperature, shaken with 5$
strength sodium carbonate solution and brine, dried over magnesium sulfate, and evaporated under vacuum.
The residue.is dissolved in 200 ml of chloroform and filtered over 2 kg of silica gel, eluting with one liter of chloroform-methanol (95:5). Yield: 210 g of the title compound as a viscous oil.
(d) N,N',N " -Tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane ____________________________________ 100 g of 1-benzyl-4,7,10-tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved in 0..5 1 of acetic acid and 0.5 1 of ethyl acetate, combined with 5 g of palladium on carbon (10~), and shaken under hydrogen for 5 hours. The mixture is removed from the catalyst by filtration, concentrated under vacuum, the residue is dissolved in one liter of chloroform, shaken with 100 ml of saturated soda solution and 100 ml of brine, dried, and evaporated under vacuum. The residue is purified by bulb tube distillation at 10 3 torr and 120° C, yielding N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane as a viscous, light-yellow oil.
Yield: 65 g.
IR (Film): 3400, 2935, 2878, 1738/cm.
1341 1 ~6 Example 1 Gadolinium(III) Complex of 1,4,7,10-Tetraazacyclo-dodecane-N,N',N " -triacetic Acid 40.25 g (100 millimoles) of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 0.5 1 of ethanol, combined with 100 ml of 3N sodium hydroxide solution, and stirred at 20° C
for 5 hours. The mixture is concentrated to 70 ml under vacuum, combined with 300 ml of water, and 2N hydro-chloric acid is added dropwise thereto up to a pH of 6.
Then the mixture is combined with 33.44 g (100 mmol) of gadolinium acetate and stirred for 3 hours at 60° C.
The solution is then first passed over an anion ex-changer "Amberlite"~'LRA 410 and then the aqueous eluate is passed over a ca~ion exchanger "Amberlite" IRC 50.
The mixture is eluted with water and the eluate evap-orated under vacuum. After drying of the residue, 35.04 g (70$ of theory) of the title compound is obtained as a colorless powder.
Anal~rsis: C14H23GdN406 (600.61) C 33.59 H 4.63 Gd 31.41 N 11.19 (calc.) 33.31 4.59 31.18 11.28 (found) Example 2 Gadolinium(III) Complex of N-(2,3-Dihydroxy-N-methyl-propylcarbamoylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N " ,N "'-triacetic Acid 55 g of N-(2,3-dihydroxy-N-methylpropyl-carbamoylmethyl)-N',N " ,N "'-tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved inØ5 1 of ethanol, combined with 96 ml of 3N sodium hydroxide solution, and stirred at 20° C for 3 hours, then concentrated under vacuum, combined with 300 ml of water and adjusted to pH 6 with 2N hydrochloric acid. To this solution is added 31.94 g of gadolinium acetate and the mixture is stirred for 18 hours at 50° C, then passed over an anion exchanger "Amberlite"
IRA 410, and subsequently the aqueous eluate is passed over a cation exchanger "Amberlite" IRC 50. The wj eluate is evaporated under vacuum and dried, thus obtaining 47.14 g (73$ of theory) of the title compound as a colorless powder.
Analysis: C20H34GdN509 (645.77) C '37.20 H 5.31 Gd 24.35 N 10.85 (calc.) 37.52 5.19 24.09 10.87 (found) The starting material for preparing the title compound according to Example 2 is obtained as follows:
(a) N,N',N " -Tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic Acid 20 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 300 ml of dichloromethane, combined with 10.40 g of triethyl-amine, and then at 0° C a solution of 4.40 g of chloroacetic acid in 100 ml of dichloromethane .
is added dropwise thereto and the mixture agitated at room temperature for 20 hours. For working-up purposes, the mixture is divided between dich.lbro-methane and phosphate buffer, pH 6, dried over magnesium sulfate, and evaporated under vacuum, yielding 23 g of the desired compound as a viscous oil.
(b) N-(2,3-Dihydroxy-N-methylpropylcarbamoylmethyl)-N',N " ,N "'-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane At 0° C, 10.5 g of triethylamine and then 14 g of chloroformic acid isobutyl ester are added dropwise to a solution of 48.86 g (100 mmol) of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid in 500 ml of dichloromethane. The mixture is stirred for one hour at 0° C and then a solution of 10.52 g of N-methylamino-2,3-propanediol in 100 ml of chloroform is added dropwise thereto and the mixture is stirred at room temperature for 2 hours. Subsequently the mixture is shaken with sodium bicarboante solution and brine, dried over magnesium sulfate, and evaporated under vacuum. For purification, the chloroform solution of the residue is filtered over 500 g of silica gel, yielding 55 g of the title compound.
r , 1341 1 7~
Example 3 Gadolinium(III) Complex of N-(N-Ethylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 24 g of N-(N-ethylcarbamoylmethyl)-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 250 ml of ethanol, combined with 47 ml of 3N sodium hydroxide solution, and stirred for 3 hours.at 20° C, then concentrated under vacuum, combined with 150 ml of water, and adjusted to pH 6 with 2N hydrochloric acid. The mixture is combined with 15.55 g of gadolinium acetate and stirred at 60° C
for 5 hours. The solution is then purified by way of ion exchangers as described in the preceding examples, thus obtaining 20.39 g of the title compound as a colorless powder.
Analysis: C18H30GdN507 (585.72) C 36.91 H 5.16 Gd 26.85 N 5.16 (calc.) 36.98 5.28 26.58 5.07 (found) Preparation of the starting material:
g (51.2 mmol) of N,N',N " -tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid (see Example 2a) is dissolved in 200 ml of dichloromethane, combined at 0° C with 5.40 g of 25 triethylamine, and subsequently with 7 g of chloroformic acid isobutyl ester. The mixture is stirred for one hour at 0° C and then a solution of 2.31 g of ethyl-amine in 20 ml of dichloromethane is added dropwise thereto. The mixture is stirred for 2 hours at room temperature, shaken with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and r evaporated to dryness under vacuum. For purification, the dichloromethane solution of the residue is filtered over 200 g of silica gel, thus obtaining 24 g of N- (N-ethylcarbamoylmethyl) -N' ,N" ,N" '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane.
Example 4 Gadolinium(III) Complex of N-Acetyl-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N " -tris(ethoxycarbonyl-methyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 mlof:dichloromethane, combined with 10 ml of pyridine, 100 mg of 4-dimethyaminopyridine, and 2.50 g of acetyl chloride, stirred at room temperature for 5 hours, combined with 1 ml of ethanol, and evap-orated under vacuum. The residue is stirred at room temperature for 5 hours with 40 ml of 1N sodium hydroxide solution, diluted with 100 ml of water, and a pH is set of 6 with 2N hydrochloric acid. Then 3.34 g of gadolinium acetate is added to the reaction mixture, and the latter is stirred at 60° C for 5 hours and the solution is subjected to purification with ion exchangers (as described in the other examples), thus obtaining 4.23 g of the title compound as a colorless powder.
Analysis: C16H25GdN407 (542.65) C 35.41 H 4.64 Gd 28.98 N 10.32 (calc.) 35.63 4.51 28.73 10.52 (found) 141 1 ~~
Example 5 Gadolinium(III) Complex of N-Ethyl-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 ml of dichloromethane, combined with 2.10 g of triethyl-amine and 3.12 g of iodoethane and, after 2 hours, the mixture is repeatedly extracted with water, dried over magnesium sulfate, and evaporated under vacuum. The residue is stirred for 6 hours with 100 ml of 1N sodium hydroxide solution, then adjusted to pH 6 with 2N
hydrochloric acid, and agitated for 16 hours with 3.34 g of gadolinium acetate at 60° C. The resultant solution is subjected to purification with ion exchangers, thus obtaining 3.70 g of the title compound as a color-less powder.
Analysis: C16H27GdN406 (528.66) C 36.35 H 5.15 Gd 29.74 N 10.60 (calc.) 36.15 5.32 29.70 10.41 (found) Example 6 Gadolinium(III) Complex of N-(2,3-Dihydroxy-1-propyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 4.30 g of N,N',N','-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 100 ml of dichloromethane, combined with 4.20 g of triethyl-amine and 2.21 g of 3-chloro-1,2-propanediol, and stirred at room temperature for 16 hours. The mix-ture is shaken with water and evaporated under vacuum.
The residue is stirred for 6 hours with 100 ml of 1N
sodium hydroxide solution, adjusted to pH 6 with 2N
hydrochloric acid, and agitated for 16 hours with 1341 17fi 3.34 g of gadolinium acetate at 50° C. The thus-obtained solution is subjected to ion exchanger purification, yielding 3.62 g of the title compound as a colorless powder.
Analysis: C17H29GdN408 (574.69) C 35.53 H 5.09 Gd 27.36 N 9.75 (calc.) 35.68 5.19 27.03 9.68 (found) Example 7 Gadolinium(III) Complex of N-(2-Aminoethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid 2.10 g of triethylamine and 1.22 g of N-(2-chloroethyl)acetamide are added to a solution of 4.30 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 100 ml of dichloro-methane. The mixture is stirred at room temperature for 18 hours, shaken with water, and evaporated under vacuum.
The residue is atirred at 60 °. C 'for= 8 .hours :with 50 .ml of 1N sodium hydroxide solution, adjusted to pH 6 with 2N hydrochloric acid, and stirred for 16 hours with 3.34 g of gadolinium acetate at 50° C. The thus-formed solution is subjected to ion exchanger purification, yielding 3.21 g of the title compound as a colorless powder.
Analysis: C16H28GdN506 (543.68) C 35.35 H 5.19 Gd 28.92 N 12.88 (calc.) 35.17 5.45 28.68 12.81 (found) 1 r 1341 1 7fi Example 8 Bis[Gadolinium(III)] Complex of 1,1'-(1,3-Propylene)-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic Acid A solution of 8.60 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 4.2 g of triethylamine in 200 ml of dichloro-methane is combined with 2.02 g of 1,3-dibromopropane and agitated for 20 hours at room temperature, shaken with water and brine, and evaporated under vacuum. The residue is fitlered with dichloromethane over 150 g of silica gel and evaporated, thus obtaining a viscous oil which is stirred with 60 ml of 1N sodium hydroxide solution for 16 hours, then diluted with 100 ml of water and adjusted to pH 6 with 2N hydrochloric acid.
After adding 6.68 g of gadolinium acetate, the mixture is stirred for 16 hours at 50° C and the solution is purified over anion and cation exchangers, thus obtain-ing 6.56 g of the title compound as a colorless powder.
Analysis: C31H50Gd2N8012 (1041.28) C 35.76 H 4.84 Gd 30.20 N 10.76 (calc.) 35.71 4.58 29.94 10.88 (found) Exam lp a 9 Bis[Gadolinium(III)] Complex of Succinyl-bis(1,4,7,10-tetraazacyclododecane-4,7,1.0-triacetic Acid) A solution of 4.30 'g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 4.20 g of triethylamine in 100 ml of dichloromethane is combined at 0° C dropwise with 1.705 g of succinic acid dichloride, dissolved in 20 ml of dichloromethane, and then the mixture is stirred for one hour at room temperature, shaken with sodium bicarbonate solution _ 48 _ '341 1 ~s and brine, and evaporated under vacuum. The residue is chromatographed on 100 g of silica gel with dichloromethane/ethyl acetate (0-30~).
A viscous oil is obtained which is stirred with 40 ml of 1N sodium hydroxide solution for 4.hours, then diluted with water (100 ml), and adjusted to pH 6 with 2N hydrochloric acid. After adding 3.34 g of gadolinium acetate, the aniXture is stirred for 16 hours at 50° C and the solution purified by way of ion exchangers, thus obtaining 3.90 g of the title compound as a white powder.
Analysis: C32H48Gd2N8014 (1083.28) C 35.48 H 4.47 Gd 29.03 N 10.34 (calc.) 35.31 4.18 28.81 10.57 (found) Example 10 Tris(Gadolinium) Complex of N6-Carboxymethyl-N3,N9-bis(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclo-dodecan-1-yl)carbonylmethyl-3,6,9-triazaundecanedioic Acid A suspension is prepared from 3.57 g of DTPA bis-anhydride in 100 ml of water and combined with 4.2 g of triethylamine and 8.61 g of N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane. The mixture is stirred at room temperature for 18 hours, combined thereafter with 200 ml of ethanol, and suctioned off from the precipitated solid matter. The filter cake is stirred with 100 ml of 1N
sodium hydroxide solution for:6 hours, then adjusted to pH 6 with 2N hydrochloric acid, 10.03 g of gadolinium acetate is added, and the mixture is stirred at 50° C for 18 hours. The solution is purified as 1341 1 ~s usual by way of ion exchangers, thus obtaining 8.32 g of the title compound as a colorless powder.
Analysis: C42H62Gd3N11020 (1512.77) C 33.35 H 4.13 Gd 31.18 N 10.18 (calc.) 33.41 4.05 31.02 10.03 (found) The preparation and isolation of complexing compounds will be demonstrated with the aid of the examples set forth below. The isolated complexing compounds can then be converted into the complexes, for example with various paramagnetic ions.
Example 11 N-(2-Hydroxyethyl)-1,4,7,10-tetraazacyclododecane-N' , N " , N " ' -triacetic Acid A solution of 6.46 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 150 ml of dichloromethane is combined with 3.2 g of triethylamine and 1.45 g of 2-chloroethanol. The mix-ture is agitated for 4 hours at room temperature, then shaken with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated under vacuum: The residue is stirred for 16 hours with 60 ml of 1N sodium hydroxide solution. By adding 5N hydrochloric acid, the pH is adjusted to 2.5.
The resultant suspension is poured on an ion ex-changer ("'DOWER"'~'S0W-X4 in the H+-form) , eluted with water and then with 0.5-molar NH3 solution, and concentrated under vacuum. The title compound is isolated by adding ethanol and suctioning off the precipitate. Yield: 4.24 g of the title compound;
purity is tested by pH titration and elementary analysis.
1341 1 ~fi Analysis: C16H30N407 (390.44) C 49.22 H 7.75 N 14.35 (calc.) 49.48 7.83 14.09 (found) Example 12 N-Methoxyacetyl-1,4,7,10-tetraazacyclododecane-N' , N " , N " ' -triacetic Acid A solution of 6.46 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 150 ml of dichloromethane is combined with 3.2 g of triethylamine and 1.79 g of methoxyacetic acid chloride.
After one hour, the mixture is shaken with soda solu-tion and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is stirred with 60 ml of 1 sodium hdyroxide solution for 5 hours at room temperature, then acidified to pH 2 by adding dilute hydrochloric acid, and the thus-obtained suspension is purified on a cation exchanger ("DOWER"
50 W-X4); elution is carried out with water and 0.5-molar NH3 solution. The eluate is concentrated and the title compound is precipitated by adding ethanol.
After suctioning and drying, 4.51 g of the title compound is obtained. Test for purity is done by titration and elementary analysis.
Analysis: C17H30N408 (418.45) C 48.80 H 7.23 N 13.39 (calc.) 48.98 7.41 13.18 (found) ~3~~ 1~s Example 13 N-[N-(2-Hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid A solution of 12.50 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid in 250 ml of dichloromethane is combined at 0° c with 5.22 g of triethylamine and then with 3.50 g of chloroformic acid isobutyl ester.
After one hour, 1.60 g of ethanolamine, dissolved in 50 ml of dichloromethane, is added dropwise, the mixture is stirred at room temperature for 2 hours, shaken with soda solution and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is chromatographed with chloroform/acetone (10:1) on 200 g of silica gel, thus obtaining 11 g of N-(2-hydroxyethyl)carbamoylmethyl-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane.
This product is stirred with 100 ml of 1N sodium hdyroxide solution for 5 hours at room temperature, then acidified with dilute hydrochloric acid to pH 2.5, and the suspension is purified on a cation exchanger ("DOWER" 50A-X4), elution being carried out with water and then with 0.5-molar NH3 solution. The eluate is extensively concentrated and, after addition of ethanol, the title compound is crystallized and isolated by filtration. Yield.
7.2 g of the title compound, the purity of which is examined by titration and elementary analysis.
Analysis: C18H33N508 (447.49) C 48.31 H 7.43 N 15.65 (calc.) 48.20 7.48 15.49 (found) 13+1 17~
Example 14 Gadolinium Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N " '-triacetic Acid Analogously to Example 2, 55.77 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with gadolinium acetate, thus obtaining 45.19 g (72~ of theory) of the title compound as a white powder.
The starting material for preparing the title compound is obtained by proceeding in analogy to Example 2b, but using morpholine in place of N-methylamino-2,3-propanediol.
., Analysis: C20H32GdN508 (627.75) ''' C 38.27 H 5.14 Gd 25.04 N 11.16 (calc.) 38.02 5.09 24.83 11.35 (found) Example 15 Gadolinium Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-tris(2-methylacetic Acid) Analogously to Example 2, 53.06 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(1-ethoxy-carbonyl-1-ethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with gadolinium acetate, thus obtaining 52.20 g (78~ of theory) of the title compound as a white powder.
1341 1 ~fi Analysis: C23H38GdN508 (669.83) C 41.24 H 5.72 Gd 23.48 N 10.46 (calc.) 41.35 5.65 23.33 10.62 (found) Example 16 Gadolinium Complex of 1-Oxa-4,7,10-triazacyclo-dodecane-N,N',N " -triacetic Acid 10.42.g of 1-oxa-4,7,10-triazacyclododecane-N,N',N " -triacetic acid and 9.85 g of gadolinium acetate are stirred with 50 ml of water at 95° C.
After about 5 minutes, a clear solution is formed which is maintained for another hour at 95° C. After cooling, the solution is stirred in succession with respectively 30 ml of cation exchanger IR 120 and anion exchanger IRA-410, filtered, and evaporated under vacuum, thus obtaining 9.17 g (61~ of theory) of the title compound as a white powder.
Analysis: C14H22GdN307 (501.59) C 33.52 H 4.42 Gd 31.35 N 8.34 (calc.) 33.63 4.50 31.18 8.42 (found) The starting material employed is obtained as follows:
13.86 g of 1-oxatriazacyclododecane is dis-solved in 200 ml of water, combined with 30.24 g of chloroacetic acid in portions and simultaneously with 9.6N potassium hydroxide solution so that the pH value of the solution remains between 9.8 and 11.8.
Then the mixture is heated for 2 hours to 100° C, while maintaining the pH value at 10.0 by further addition of potassium hydroxide solution. After cooling to 20° C, the mixture is adjusted to pH 2 by adding 26.5 ml of 12N hydrochloric acid and poured on 1.6 1 of cation exchanger IR 120 and eluted with 4.8 1 of water.
This eluate is discarded. Elution is continued with 1.2 1 of 0.5N ammonia and the mixture evaporated under vacuum, thus obtaining 24.1 g of 1-oxa-4,7,10-triaza-cyclododecane-N,N',N " -triacetic acid (86.8 of theory), mp 68-70° C.
Example 17 Bis(Gadolinium) Complex of 1,1'-(2-Hydroxy-1,3-propylene)-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic Acid) A solution of 43.05 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 450 ml of dimethylformamide is combined with 4.63 g of epichlorohydrin. After one hour, the mix-ture is combined with 7.5 g of sodium iodide and heated for 24 hours to 80° C, concentrated under vacuum, and the residue divided between water and chloroform. The chloroform phase is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on 1 kg of silica gel with dichloromethane.- 10~ acetone, thus obtaining 27.5 g of l,1'-(2-hydroxy-1,3-propylene)-bis-(1,4,7,10-tetraazacyclododecanetriacetic acid ethyl ester) as a viscous oil.
9.17 g of the thus-prepared ester is dis-solved in 200 ml of ethanol and stirred with 30 ml of 3N sodium hydroxide solution for 20 hours at room temperature; then a pH of 6 is set with hydro-chloric acid and the mixture stirred for 16 hours at 60° C with 6.68 g of gadolinium acetate. The solu-tion is purified over anion and cation exchangers, yielding 10.05 g of the title compound as a white powder.
' ' 1341 176 Analysis: C31H50Gd2N8013 (1057.28) C 35.22 H 4.77 Gd 29.75 N 10.60 (calc.) 35.03 4.89 29.49 10.41 (found) Example 18 N-Methylglucamine Salt of the Manganese(II) Complex of N-[N-(2-Hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 8. 95 g ( 20 mmol) of N- [N- ( 2-hydroxyethyl) -carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic acid is suspended in 30 ml of water and heated with 1.40 g (20 mmol) of manganese(II) oxide to 100° C for 3 hours. Then the mixture is combined with 3.90 g (20 mmol.) of N-methylglucamine, heated for another 12 hours to 100° C, and the solution is evaporated to dryness under vacuum, thus obtaining e'; 13.8 g of the title compound as a pink powder, mp 140-143° C.
Analysis: C25H48MnN6013 (695.64) C 43.17 H 6.96 Mn 7.90 N 12.08 (calc..) 43.44 7.16 7.69 12.01 (found) Example 19 Dysprosium(III) Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid Analogously to Example 2, 20 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with dysprosium acetate, thus obtaining 16.3 g of the title compound as a white powder.
141 1~6 Analysis: C20H32DyN508 (633.01) C 37.95 H 5.10 Dy 25.67 N 11.06 (calc.) 37.71 4.92 25.81 11.32 (found) Example 20 Preparation of Liposomes Loaded with Gadolinium N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N " ,N " '-triacetic Acid In accordance with the procedure described in Proc. Natl. Acad. Sci. U.S.A. _75 . 4194, a lipid mixture is made up from 75 mol-$ egg phosphatidylcholine and 25 mol-g cholesterol as the dry substance. Of this quantity, 500 mg is dissolved in 30 ml of diethyl ether and, in an ultrasonic bath, combined dropwise with 3 ml of an aqueous 0.1-molar solution of the gadolinium complex of N-(morpholinocarbonylmethyl)-1,4,7,10-tetraaza-N',N " ,N " '-triacetic acid. The ultrasonic treatment is continued for 10 minutes and the mixture is concentrated under vacuum. The gelatin-like residue is suspended in 0.125-molar sodium chloride solution and at 0° C repeatedly centrifuged at 20,000 g in order to separate unencapsulated gadolinium complex.
The suspension is then subjected to freeze-drying in multivials. Administration takes place as a colloidal dispersion in 0.9$ strength sodium chloride solution.
Example 21 Preparation of a Solution of the Yttrium-90 Complex of the Conjugate of 1,4,7,10-Tetraazacyclododecane-N,N',N " ,N " '-tetraacetic Acid with Monoclonal Antibodies A suspension of 4 mg of 1,4,7,10-tetraaza-cyclododecane-N,N',N " ,N " '-tetraazacyclododecane-N,N',N " ,N " '-tetraacetic acid in 1 ml of water is combined with 2 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and then with l mi of a solution of 0.6 mg of monoclonal:. antibody (with specificity against melanoma antigen) in 0.05-molar sodium bicarbonate buffer (pH 7.8). The mixture is stirred for 2 hours at room temperature and dialyzed against a 0.3-molar sodium phosphate buffer. Then 1 ml of an Yttrium-90 solution in acetate buffer pH 6 is added (prepared according to Int. J. Appl. Radiat.
Isot., 36 . 803 [1985]) and the mixture is incubated for 24 hours at room temperature. The solution ~~ passed through a "Sephadex"'r"'G 25 column and the radioactive protein fraction is filtered under sterile conditions and dispensed into multivials. By lyophilization, a dry preparation that can be stored is obtained.
Example 22 Gadolinium Complex of N-(Isopropoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N " '-triacetic Acid At 0° C, 10.5 g of triethylamine is added dropwi.se to a solution of 48.86 g (100 mmol) of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane-N " '-acetic acid in 500 ml of dichloromethane, and then 14 g of chloroformic acid isobutyl ester is added. The mix-ture is stirred for one hour at 0° C and then t~
' ' . 1341 17fi 6.61 g of isopropyl alcohol is added dropwise and the mixture stirred for 4 hours at room temperature, shaken with sodium bicarbonate and brine, and evaporated under vacuum. For purification, the chloroform solution of the residue is filtered over 500 g of silica gel, thus obtaining 45.0 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid iso-propyl ester as a light-yellow, viscous oil.
A solution is made up from 10.61 g (20 mmol) of the thus-produced isopropyl ester in 150 ml of ethanol and at 0° C is combined during the course of 5 hours with 60 ml of 1N sodium hydroxide solution.
The mixture is stirred for another hour at 0° C, then adjusted to pH 6 with 2N hydrochloric acid, and ex-tensively concentrated under vacuum. Then the mixture is diluted with 200 ml of water, combined with 6.69 g of gadolinium acetate, and heated for 16 hours to 50° C.
The solution is then subjected to an ion exchanger purification, yielding 8.20 g of the title compound as a colorless powder.
Analysis: C19H31GdN408 (600.73) C 37.99 H 5.20 Gd 26.18 N 9.33 (calc.) 38.22 5.31 26.02 9.41 (found) Example 23 Indium-111 Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N ",N " '-triacetic Acid The process is performed analogously to Example 14, forming the complex compound with radio-active lllindium chloride. In order to ascertain whether the metal ions are completely bound as a chelate, the solution of the title compound is examined by thin-layer chromatography on silica gel plates in the system methanol-water (2:1). Metal ions that have not been chelated are recognized herein as a.radioactive zone at the starting spot. If necessary, chelating is completed by the further addition of N-(morpholino-carbonylmethyl)-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and subsequent ester cleavage.
In the same way, the gadolinium-153 complex of N-(morpholinocarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane-N',N " ,N " '-triacetic acid is obtained.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
S From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Analysis: C18H33N508 (447.49) C 48.31 H 7.43 N 15.65 (calc.) 48.20 7.48 15.49 (found) 13+1 17~
Example 14 Gadolinium Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N " '-triacetic Acid Analogously to Example 2, 55.77 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with gadolinium acetate, thus obtaining 45.19 g (72~ of theory) of the title compound as a white powder.
The starting material for preparing the title compound is obtained by proceeding in analogy to Example 2b, but using morpholine in place of N-methylamino-2,3-propanediol.
., Analysis: C20H32GdN508 (627.75) ''' C 38.27 H 5.14 Gd 25.04 N 11.16 (calc.) 38.02 5.09 24.83 11.35 (found) Example 15 Gadolinium Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-tris(2-methylacetic Acid) Analogously to Example 2, 53.06 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(1-ethoxy-carbonyl-1-ethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with gadolinium acetate, thus obtaining 52.20 g (78~ of theory) of the title compound as a white powder.
1341 1 ~fi Analysis: C23H38GdN508 (669.83) C 41.24 H 5.72 Gd 23.48 N 10.46 (calc.) 41.35 5.65 23.33 10.62 (found) Example 16 Gadolinium Complex of 1-Oxa-4,7,10-triazacyclo-dodecane-N,N',N " -triacetic Acid 10.42.g of 1-oxa-4,7,10-triazacyclododecane-N,N',N " -triacetic acid and 9.85 g of gadolinium acetate are stirred with 50 ml of water at 95° C.
After about 5 minutes, a clear solution is formed which is maintained for another hour at 95° C. After cooling, the solution is stirred in succession with respectively 30 ml of cation exchanger IR 120 and anion exchanger IRA-410, filtered, and evaporated under vacuum, thus obtaining 9.17 g (61~ of theory) of the title compound as a white powder.
Analysis: C14H22GdN307 (501.59) C 33.52 H 4.42 Gd 31.35 N 8.34 (calc.) 33.63 4.50 31.18 8.42 (found) The starting material employed is obtained as follows:
13.86 g of 1-oxatriazacyclododecane is dis-solved in 200 ml of water, combined with 30.24 g of chloroacetic acid in portions and simultaneously with 9.6N potassium hydroxide solution so that the pH value of the solution remains between 9.8 and 11.8.
Then the mixture is heated for 2 hours to 100° C, while maintaining the pH value at 10.0 by further addition of potassium hydroxide solution. After cooling to 20° C, the mixture is adjusted to pH 2 by adding 26.5 ml of 12N hydrochloric acid and poured on 1.6 1 of cation exchanger IR 120 and eluted with 4.8 1 of water.
This eluate is discarded. Elution is continued with 1.2 1 of 0.5N ammonia and the mixture evaporated under vacuum, thus obtaining 24.1 g of 1-oxa-4,7,10-triaza-cyclododecane-N,N',N " -triacetic acid (86.8 of theory), mp 68-70° C.
Example 17 Bis(Gadolinium) Complex of 1,1'-(2-Hydroxy-1,3-propylene)-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic Acid) A solution of 43.05 g of N,N',N " -tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane in 450 ml of dimethylformamide is combined with 4.63 g of epichlorohydrin. After one hour, the mix-ture is combined with 7.5 g of sodium iodide and heated for 24 hours to 80° C, concentrated under vacuum, and the residue divided between water and chloroform. The chloroform phase is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on 1 kg of silica gel with dichloromethane.- 10~ acetone, thus obtaining 27.5 g of l,1'-(2-hydroxy-1,3-propylene)-bis-(1,4,7,10-tetraazacyclododecanetriacetic acid ethyl ester) as a viscous oil.
9.17 g of the thus-prepared ester is dis-solved in 200 ml of ethanol and stirred with 30 ml of 3N sodium hydroxide solution for 20 hours at room temperature; then a pH of 6 is set with hydro-chloric acid and the mixture stirred for 16 hours at 60° C with 6.68 g of gadolinium acetate. The solu-tion is purified over anion and cation exchangers, yielding 10.05 g of the title compound as a white powder.
' ' 1341 176 Analysis: C31H50Gd2N8013 (1057.28) C 35.22 H 4.77 Gd 29.75 N 10.60 (calc.) 35.03 4.89 29.49 10.41 (found) Example 18 N-Methylglucamine Salt of the Manganese(II) Complex of N-[N-(2-Hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetra-azacyclododecane-N',N " ,N " '-triacetic Acid 8. 95 g ( 20 mmol) of N- [N- ( 2-hydroxyethyl) -carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic acid is suspended in 30 ml of water and heated with 1.40 g (20 mmol) of manganese(II) oxide to 100° C for 3 hours. Then the mixture is combined with 3.90 g (20 mmol.) of N-methylglucamine, heated for another 12 hours to 100° C, and the solution is evaporated to dryness under vacuum, thus obtaining e'; 13.8 g of the title compound as a pink powder, mp 140-143° C.
Analysis: C25H48MnN6013 (695.64) C 43.17 H 6.96 Mn 7.90 N 12.08 (calc..) 43.44 7.16 7.69 12.01 (found) Example 19 Dysprosium(III) Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N " ,N " '-triacetic Acid Analogously to Example 2, 20 g of N-(morpholinocarbonylmethyl)-N',N " ,N " '-tris(ethoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane is hydrolyzed with sodium hydroxide solution and complexed with dysprosium acetate, thus obtaining 16.3 g of the title compound as a white powder.
141 1~6 Analysis: C20H32DyN508 (633.01) C 37.95 H 5.10 Dy 25.67 N 11.06 (calc.) 37.71 4.92 25.81 11.32 (found) Example 20 Preparation of Liposomes Loaded with Gadolinium N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N " ,N " '-triacetic Acid In accordance with the procedure described in Proc. Natl. Acad. Sci. U.S.A. _75 . 4194, a lipid mixture is made up from 75 mol-$ egg phosphatidylcholine and 25 mol-g cholesterol as the dry substance. Of this quantity, 500 mg is dissolved in 30 ml of diethyl ether and, in an ultrasonic bath, combined dropwise with 3 ml of an aqueous 0.1-molar solution of the gadolinium complex of N-(morpholinocarbonylmethyl)-1,4,7,10-tetraaza-N',N " ,N " '-triacetic acid. The ultrasonic treatment is continued for 10 minutes and the mixture is concentrated under vacuum. The gelatin-like residue is suspended in 0.125-molar sodium chloride solution and at 0° C repeatedly centrifuged at 20,000 g in order to separate unencapsulated gadolinium complex.
The suspension is then subjected to freeze-drying in multivials. Administration takes place as a colloidal dispersion in 0.9$ strength sodium chloride solution.
Example 21 Preparation of a Solution of the Yttrium-90 Complex of the Conjugate of 1,4,7,10-Tetraazacyclododecane-N,N',N " ,N " '-tetraacetic Acid with Monoclonal Antibodies A suspension of 4 mg of 1,4,7,10-tetraaza-cyclododecane-N,N',N " ,N " '-tetraazacyclododecane-N,N',N " ,N " '-tetraacetic acid in 1 ml of water is combined with 2 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and then with l mi of a solution of 0.6 mg of monoclonal:. antibody (with specificity against melanoma antigen) in 0.05-molar sodium bicarbonate buffer (pH 7.8). The mixture is stirred for 2 hours at room temperature and dialyzed against a 0.3-molar sodium phosphate buffer. Then 1 ml of an Yttrium-90 solution in acetate buffer pH 6 is added (prepared according to Int. J. Appl. Radiat.
Isot., 36 . 803 [1985]) and the mixture is incubated for 24 hours at room temperature. The solution ~~ passed through a "Sephadex"'r"'G 25 column and the radioactive protein fraction is filtered under sterile conditions and dispensed into multivials. By lyophilization, a dry preparation that can be stored is obtained.
Example 22 Gadolinium Complex of N-(Isopropoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N " '-triacetic Acid At 0° C, 10.5 g of triethylamine is added dropwi.se to a solution of 48.86 g (100 mmol) of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetra-azacyclododecane-N " '-acetic acid in 500 ml of dichloromethane, and then 14 g of chloroformic acid isobutyl ester is added. The mix-ture is stirred for one hour at 0° C and then t~
' ' . 1341 17fi 6.61 g of isopropyl alcohol is added dropwise and the mixture stirred for 4 hours at room temperature, shaken with sodium bicarbonate and brine, and evaporated under vacuum. For purification, the chloroform solution of the residue is filtered over 500 g of silica gel, thus obtaining 45.0 g of N,N',N " -tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N " '-acetic acid iso-propyl ester as a light-yellow, viscous oil.
A solution is made up from 10.61 g (20 mmol) of the thus-produced isopropyl ester in 150 ml of ethanol and at 0° C is combined during the course of 5 hours with 60 ml of 1N sodium hydroxide solution.
The mixture is stirred for another hour at 0° C, then adjusted to pH 6 with 2N hydrochloric acid, and ex-tensively concentrated under vacuum. Then the mixture is diluted with 200 ml of water, combined with 6.69 g of gadolinium acetate, and heated for 16 hours to 50° C.
The solution is then subjected to an ion exchanger purification, yielding 8.20 g of the title compound as a colorless powder.
Analysis: C19H31GdN408 (600.73) C 37.99 H 5.20 Gd 26.18 N 9.33 (calc.) 38.22 5.31 26.02 9.41 (found) Example 23 Indium-111 Complex of N-(Morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N ",N " '-triacetic Acid The process is performed analogously to Example 14, forming the complex compound with radio-active lllindium chloride. In order to ascertain whether the metal ions are completely bound as a chelate, the solution of the title compound is examined by thin-layer chromatography on silica gel plates in the system methanol-water (2:1). Metal ions that have not been chelated are recognized herein as a.radioactive zone at the starting spot. If necessary, chelating is completed by the further addition of N-(morpholino-carbonylmethyl)-N',N " ,N " '-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and subsequent ester cleavage.
In the same way, the gadolinium-153 complex of N-(morpholinocarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane-N',N " ,N " '-triacetic acid is obtained.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
S From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (15)
1. A 1,4,7,10-tetraazacyclododecane of Formula II
wherein:
each R1, independently of each other, is hydrogen or metal ion equivalent of a complexible metal;
R2 is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is or -COOR6, wherein R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon atoms, C6-10-aryl or C6-10-ar-C104-alkyl, or R2 or R3 represent a second macrocycle of Formula II', which is of a structure the same as or different from that of the basic skeleton of Formula II, linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or R2 is B or CH2-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor.
wherein:
each R1, independently of each other, is hydrogen or metal ion equivalent of a complexible metal;
R2 is a linear or branched, saturated or unsaturated hydrocarbyl, acyl or acyl-alkylene group each of 1-16 carbon atoms substituted by from 1 to 10 hydroxy or lower alkoxy groups, -CH2-X-V wherein X is carbonyl, alkylene of 0-10 carbon atoms, optionally substituted by hydroxy and/or lower alkoxy, or alkylene of 5-23 carbon atoms interrupted by oxygen atoms, V is or -COOR6, wherein R3 and R4, independently of each other, each is hydrogen, alkyl of 1-16 carbon atoms, or alkyl of 1-16 C-atoms substituted by hydroxy and/or lower alkoxy, or R3 and R4 together with the connecting nitrogen atom form a five- or six-membered saturated ring which can also contain an additional hetero N, S
or O atom, and R6 is aliphatic hydrocarbyl of up to 16 carbon atoms, C6-10-aryl or C6-10-ar-C104-alkyl, or R2 or R3 represent a second macrocycle of Formula II', which is of a structure the same as or different from that of the basic skeleton of Formula II, linked by way of an alkylene chain containing 2-20 carbon atoms which optionally carries carbonyl groups at its ends and/or optionally is interrupted by oxygen or R1-carboxymethylimino and/or optionally is substituted by hydroxy, lower alkoxy or carboxy-lower alkyl, or R2 is B or CH2-COB, wherein B is a biomolecule or synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor.
2. A compound of claim 1, wherein R1 in each case is hydrogen.
3. A compound of claim 1, wherein at least two of the substituents R1 are metal ion equivalents of at least one metal of atomic numbers 21-29, 42, 44 or 57-70.
4. A compound of claim 1, wherein at least two of the substituents R1 are metal ion equivalents of at least one radionuclide of an element of atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 64, 70 or 77.
5. A compound of any one of claims 1 to 4, wherein R2 is amidomethylene, N-R'- or N,N-diR'-amidomethylene wherein each R' independently is alkyl or alkyl substituted by 1-4 OH groups, C1-4-alkylcarbonyl, C1-4-alkyl, C1-4-alkyl substituted by 1-4 OH groups or amino, C1-4-alkoxy-C1-4-alkonoyl, C1-4-alkoxy-C1-4-alkanoyl-C1-4-alkylene, or N,N-diR"-amido-C1-4-alkylene, wherein the R" groups and the connecting N-atom form a five- or six-membered saturated ring or such a ring containing an additional N-atom or S or O.
6. A compound of any one of claims 1 to 5, containing a macromolecule B which is a biomolecule or a synthetic polymer that accumulates to an especially great extent in the organ or organ part to be investigated or in a tumor.
7. A compound of claim 1 which is N-(2,3-dihydroxy-N-methylpropylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetic acid, N-(N-ethylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetic acid, N-acetyl-1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetic acid, N-(2,3-dihydroxy-1-propyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, 1,1'-(1,3-propylene)bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid), succinyl-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid), N6-carboxymethyl-N3,N9-bis(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)carbonylmethyl-3,6,9-triazaundecanedioic acid, N-(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-methoxyacetyl-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-[N-(2-hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclodo-decane-N', N'', N'''-triacetic acid, N-(morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N'',N'''-tris(2-methylacetic acid), 1,1'-(2-hydroxy-1,3-propylene)bis(1,4,7,10-tetra-azacyclododecane-4,7,10-triacetic acid), N-(isopropoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N'',N'''-triacetic acid, or a complex thereof with a paramagnetic metal or a radioisotope.
8. A gadolinium, manganese or dysprosium complex of N-(2,3-dihydroxy-N-methylpropylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(N-ethylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-acetyl-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(2,3-dihydroxy-1-propyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, 1,1'-(1,3-propylene)bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid), succinyl-bis(1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid), N6-carboxymethyl-N3,N9-bis(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)carbonylmethyl-3,6,9-triazaundecanedioic acid, N-(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-methoxyacetyl-1,4,7,10-tetraazacyclododecane- N',N'',N'''-triacetic acid, N-[N-(2-hydroxyethyl)carbamoylmethyl]-1,4,7,10-tetraazacyclododecane-N',N'',N'''-triacetic acid, N-(morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclododecane-N',N",N"'-triacetic acid, N-(morpholinocarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N'',N'''-tris(2-methylacetic acid), 1,1'-(2-hydroxy-1,3-propylene)bis(1,4,7,10-tetra-azacyclododecane-4,7,10-triacetic acid), or N-(isopropoxycarbonylmethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N'',N'''-triacetic acid.
9. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier in liquid phase, and from 1µ mol to 1 mol of a compound of any one of claims 1 to 8, per liter overall.
10. A pharmaceutical composition useful as a diagnostic agent, comprising a compound of claim 1, 3 or 4, wherein at least two of R1 are a metal ion equivalent, and a pharmaceutically-acceptable carrier.
11. In a method of making an NMR image of a patient comprising administering to the patient an agent effective to enhance an NMR image, the improvement wherein said agent is a compound of claim 1 or 3, and at least two of R1 are metal ion equivalents of a paramagnetic ion.
12. In a method of making an X-ray image of a patient comprising administering to the patient an agent effective to enhance an X-ray image, the improvement wherein said agent is a compound of claim 1, 3 or 4, and at least two of R1 are metal ion equivalents of an ion having an X-ray cross-section whereby an X-ray image is enhanced.
13. In a method of making an ultrasonic image of a patient comprising administering to the patient an agent effective to enhance an ultrasonic image, the improvement wherein said agent is a compound of claim 1, 3 or 4, and at least two of R1 are metal ion equivalents of an ion effective to enhance an ultrasonic image.
14. In a method of making a radiodiagnostic image of a patient comprising administering to the patient an agent effective to enhance a radiodiagnostic image, the improvement wherein said agent is a compound of claim 1 or 4, and at least two of R1 are metal ion equivalents of a radioactive ion.
15. Use in radiotherapy of a compound of claim 1 or 3, wherein at least two of R1 are metal ion equivalents of a radioactive metal.
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GB8603537D0 (en) * | 1986-02-13 | 1986-03-19 | Parker D | Conjugate compound |
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1986
- 1986-07-28 DE DE3625417A patent/DE3625417C2/en not_active Expired - Lifetime
-
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- 1987-07-24 ES ES87730085T patent/ES2052599T3/en not_active Expired - Lifetime
- 1987-07-24 EP EP87730085A patent/EP0255471B1/en not_active Expired - Lifetime
- 1987-07-24 AT AT87730085T patent/ATE80391T1/en not_active IP Right Cessation
- 1987-07-24 DE DE8787730085T patent/DE3781620D1/en not_active Expired - Lifetime
- 1987-07-27 CA CA000543027A patent/CA1341176C/en not_active Expired - Lifetime
- 1987-07-27 PT PT85410A patent/PT85410B/en unknown
- 1987-07-27 NO NO873132A patent/NO174048C/en not_active IP Right Cessation
- 1987-07-28 DK DK393387A patent/DK171574B1/en not_active IP Right Cessation
- 1987-07-28 IE IE203887A patent/IE60677B1/en not_active IP Right Cessation
- 1987-07-28 JP JP62186794A patent/JPH0753720B2/en not_active Expired - Lifetime
- 1987-07-28 ZA ZA875561A patent/ZA875561B/en unknown
- 1987-07-28 NZ NZ221225A patent/NZ221225A/en unknown
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Also Published As
Publication number | Publication date |
---|---|
ATE80391T1 (en) | 1992-09-15 |
DK393387A (en) | 1988-01-29 |
IE872038L (en) | 1988-01-28 |
DE3781620D1 (en) | 1992-10-15 |
DE3625417A1 (en) | 1988-02-11 |
JPH0753720B2 (en) | 1995-06-07 |
NO873132D0 (en) | 1987-07-27 |
EP0255471A1 (en) | 1988-02-03 |
GR3005808T3 (en) | 1993-06-07 |
PT85410A (en) | 1987-08-01 |
DK393387D0 (en) | 1987-07-28 |
EP0255471B1 (en) | 1992-09-09 |
AU7621787A (en) | 1988-02-04 |
IE60677B1 (en) | 1994-08-10 |
DE3625417C2 (en) | 1998-10-08 |
JPS6341468A (en) | 1988-02-22 |
AU604249B2 (en) | 1990-12-13 |
NO174048B (en) | 1993-11-29 |
NO174048C (en) | 1994-03-09 |
PT85410B (en) | 1990-06-29 |
DK171574B1 (en) | 1997-01-20 |
NZ221225A (en) | 1990-09-26 |
NO873132L (en) | 1988-01-29 |
ZA875561B (en) | 1989-03-29 |
ES2052599T3 (en) | 1994-07-16 |
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