WO1993015093A1 - Specific contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system - Google Patents
Specific contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system Download PDFInfo
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- WO1993015093A1 WO1993015093A1 PCT/US1992/000678 US9200678W WO9315093A1 WO 1993015093 A1 WO1993015093 A1 WO 1993015093A1 US 9200678 W US9200678 W US 9200678W WO 9315093 A1 WO9315093 A1 WO 9315093A1
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- Prior art keywords
- phenyl
- complex according
- carbon atoms
- substituted
- amino
- Prior art date
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- 238000002595 magnetic resonance imaging Methods 0.000 title claims description 18
- 239000002872 contrast media Substances 0.000 title abstract description 19
- 210000000813 small intestine Anatomy 0.000 title abstract description 17
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 60
- -1 nitro, amino, sulfonyl Chemical group 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 150000004696 coordination complex Chemical class 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Chemical group 0.000 claims description 7
- 238000002405 diagnostic procedure Methods 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims 12
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 11
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 6
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims 4
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims 3
- 229910052742 iron Inorganic materials 0.000 claims 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 230000002708 enhancing effect Effects 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical class CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 abstract description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 9
- 229960000958 deferoxamine Drugs 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 210000000941 bile Anatomy 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- DNWAYXNMUKHONN-UHFFFAOYSA-N 4-phenyloxane-2,6-dione Chemical compound C1C(=O)OC(=O)CC1C1=CC=CC=C1 DNWAYXNMUKHONN-UHFFFAOYSA-N 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 210000003608 fece Anatomy 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000005298 paramagnetic effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000005561 phenanthryl group Chemical class 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- ROUACTHMBRMGKZ-UHFFFAOYSA-J 2-[2-[[carboxylato-(2-oxidophenyl)methyl]amino]ethylamino]-2-(2-oxidophenyl)acetate;iron(3+) Chemical compound [Fe+3].C=1C=CC=C([O-])C=1C(C(=O)[O-])NCCNC(C([O-])=O)C1=CC=CC=C1[O-] ROUACTHMBRMGKZ-UHFFFAOYSA-J 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- BQBMBPVXNBHWBM-UHFFFAOYSA-N 3-(4-chlorophenyl)oxane-2,6-dione Chemical compound C1=CC(Cl)=CC=C1C1C(=O)OC(=O)CC1 BQBMBPVXNBHWBM-UHFFFAOYSA-N 0.000 description 1
- IELMEAGZPYTZFN-UHFFFAOYSA-N 3-(4-nitrophenyl)oxane-2,6-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1C(=O)OC(=O)CC1 IELMEAGZPYTZFN-UHFFFAOYSA-N 0.000 description 1
- MOEVYBHRQCRAJH-UHFFFAOYSA-N 3-(4-propan-2-ylphenyl)oxane-2,6-dione Chemical compound C1=CC(C(C)C)=CC=C1C1C(=O)OC(=O)CC1 MOEVYBHRQCRAJH-UHFFFAOYSA-N 0.000 description 1
- BKXQZROPJLVQMW-UHFFFAOYSA-N 3-(4-tert-butylphenyl)oxane-2,6-dione Chemical compound C1=CC(C(C)(C)C)=CC=C1C1C(=O)OC(=O)CC1 BKXQZROPJLVQMW-UHFFFAOYSA-N 0.000 description 1
- FJTWTGLRBXSCMW-UHFFFAOYSA-N 3-[4-(trichloromethyl)phenyl]oxane-2,6-dione Chemical compound C1=CC(C(Cl)(Cl)Cl)=CC=C1C1C(=O)OC(=O)CC1 FJTWTGLRBXSCMW-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 0 C*1(C)CCCC1 Chemical compound C*1(C)CCCC1 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000007630 basic procedure Methods 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 230000005294 ferromagnetic effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940073585 tromethamine hydrochloride Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910000859 α-Fe Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
Definitions
- the present invention is directed to a novel class of carboxylic acid derivatives of the iron (III) chelate of desferrioxamine B which are useful as magnetic resonance imaging contrast agents for renal, hepatobiliary and, in particular, small intestine image enhancement.
- the iron (III) chelate of desferrioxamine B is a known magnetic resonance imaging contrast agent that gives both renal and hepatobiliary enhancement. It is one of the soluble paramagnetic compounds used for this purpose.
- Other soluble paramagnetic compounds, such as Gd-DTPA suffer from various disadvantages, such as, rapid diffusion from the vascular system into the extracellular space, lack of specificity for liver and essentially no concentration in the bile.
- Manganese dichloride concentrates in the liver after IV injection. is transported to the bile and excreted in the feces. However, it is toxic and is not practically useful in a clinical situation.
- Iron (III) complexes Fe-EHPG and Fe-HBED are useful contrast agents in the liver and are secreted into the bile. However, their appearance in the bile does not take place until approximately 20 minutes post injection and furthermore, enhancement of the lumen of the small intestine is seldom observed using these agents.
- the magnetic resonance imaging of the gastrointestinal tract is limited by inherently low image contrast, motion and variable anatomic appearance. Agents for this purpose are normally administered orally and reside within lumen of the GI tract to provide either positive (increased signal strength) or negative (decreased signal strength) contrast.
- positive contrast is provided by ingestion of paramagnetic agents .
- paramagnetic agents such as Gd-DTPA or iron citrate
- negative contrast is provided by displacement of the luminal proton-containing contents by gas (such as carbon dioxide from gas tablets) or perfluorocarbons.
- Negative contrast can also be obtained by ingestion of ferromagnetic or superparamagnetic particles, such as ferrite.
- MRI contrast agents which are useful both for hepatobiliary studies and for gastrointestinal studies, particularly when introduced by intravenous administration, rather than by oral administration. It is thus an object of the present invention to provide improved desferrioxamine B contrast agents for magnetic resonance imaging. It is yet another object of the present invention to provide magnetic resonance imaging contrast agents having high stability, low toxicity, physiological tolerability and which provide for positive imaging of the small intestine rapidly after intravenous administration.
- the present invention provides a method for performing magnetic resonance imaging diagnostic procedures in a subject comprising the step of administering intravenously to the subject a magnetic resonance imaging enhancement effective amount of a diagnostic medium comprising the compound of the following formula in a physiologically acceptable carrier:
- R is -desferrioxamine B
- j is an integer from 1 to n
- k is an integer from O to m
- s is an integer from 0 to p
- p+n+m is less than or equal to 18
- each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k , R 7 s and R 8 s is independently hydrogen, aryl or substituted ary
- FIGS. 1A through IE are graphs showing the distribution of 59 Fe in labelled contrast agents, DF, GDF, PSDF, SDF and PGDF, respectively.
- Media according to the present invention are useful for magnetic resonance imaging diagnosis.
- Production of the diagnostic media according to the present invention may be performed according to ways known in the art, i.e., by forming a complex salt as described hereinbelow, optionally with the addition of customary additives such as galenicals, which may be suspended or dissolved in an aqueous medium followed by sterilization.
- Suitable additives include, for example, physiologically biocompatible buffers such as tromethamine hydrochloride, complexing agents such as diethylenediiaminepentaacetic acid, or if necessary electrolytes such as sodium chloride.
- the compounds according to the present invention which are utilized in the present method are those of the following formula I: wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from O to m; s is an integer from 0 to p; p+n+m is less than or equal to 18; each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k
- aryl groups are phenyl, substituted phenyl, biphenyl, substituted biphenyl, phenanthryl, anthracyl, substituted phenanthryl.
- a more preferred aryl group or aryloxy group are phenyl and phenoxy and preferably para substituted phenyl or phenoxy.
- a second class of complexes are those comprising a metal ion selected from the group consisting of Fe (III), Dy (III), Gd (III), Cr (III) and Mn (II) and a ligand of the formula (III)
- R is -desferrioxamine-B; t and u are integers from 0 to 3 ; R ⁇ is hydroxy or an alkoxy of 1 to 18 carbon atoms or an aryloxy of 6 to 14 carbon atoms, or substituted aryloxy having at least one substituent selected from the group consisting of aryl, nitro, sulfonyl, hydroxl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxy carbonyl of 2 to 6 carbon atoms and sulfhydryl.
- Components of the above formula may be made by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of an aromatic dicarboxylic acid, such as phthalic anhydride.
- anhydride of an aromatic dicarboxylic acid such as phthalic anhydride.
- the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative.
- Any -O- esters that may have formed during the amidation reaction may. then be removed under conventional conditions to result in the N-carboxylated desferrioxamine B contrast agents according to the present invention.
- Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C in a suitable solvent, such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the NOH groups may be protected by esterification or by complexation with a metal ion.
- the preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
- radical desferrioxamine B is of the following formula II
- the active ingredient of the contrast agents according to the present invention are generally prepared by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of a dicarboxylic acid.
- a salt of desferrioxamine B such as the mesylate
- an appropriate anhydride of a dicarboxylic acid By using two or more equivalents of the anhydride to one equivalent of the protected desferrioxamine B, in a basic medium, the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative. Any -O- esters that may have formed during the amidation reaction may then be removed under conventional conditions to result in the N-carboxylated; desferrioxamine B contrast agents according to the present invention.
- Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C, in a suitable solvent, such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the N-OH groups may be protected by esterification or by complexation with a metal ion.
- the preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
- Preferred ligands are shown in Table 1.
- the N-(3-phenylglutaramido) desferrioxamine B iron (III) complex is advantageously used for MRI imaging of the small intestine.
- N-carboxylated desferrioxamine B ligands and complexes thereof with metals according to the present invention having the following formula are novel.
- R is -desferrioxamine B
- j is an integer from 1 to n
- k is an integer from 0 to m
- s is an integer from 0 to p
- p+n+m is less than or equal to 18
- each R 1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R 2 j , R 3 k , R 4 k , R 7 s and R 8 s is independently hydrogen, aryl or substituted
- the contrast agents according to the present invention are particularly advantageous in that upon intravenous injection, they concentrate in bile, and in some cases, appear in the small intestine very rapidly, usually within about two minutes post injection. They are useful in that they may be administered by the intravenous route, thus the entry into the small intestine is by the hepatobiliary system. Therefore, in addition to contrast enhancement of alimentary tract lumen, with its resulting increased anatomical information, the contrast agents also provide functional information. For example, hepatobiliary dysfunctions, such as bile duct occlusion will retard, lessen or prevent the transport of the contrast agent and thus be revealed by MRI.
- the contrast agents according to the present invention not only show specificity for the biliary system and small intestines, but they also are relatively non-toxic and substantially completely excreted.
- Conventional hepatobiliary contrast agents, such as Gd-DTPA distribute in the extracellular volume and are not useful therefore for imaging the small intestine.
- the reagents according to the present invention therefore can reveal additional details regarding the anatomy of the small intestines, and because of their very rapid localization in the bile and gut lumen, the MRI of these organ systems are simplified and thereby expedited.
- metal ions besides iron (III) may be utilized to complex with the ligands according to the present invention for use in magnetic resonance imaging.
- Useful metal ions include Dy (III), Gd (III), Cr (III), and Mn (II).
- the agents according to the present invention are utilized preferably in solutions made by addition of a solvent such as water, serum, albumin solutions, or saline to the complex.
- a typical injectable composition will contain about 10 mg/ml human serum albumin with a metal complex concentration of about 20 to 200 mg/ml.
- a 0.1 m phosphate buffer (7.5 pH) may be employed containing, for example, about 0.9% sodium chloride.
- the pH of the aqueous solutions may range between about 5 to 9 over a volume range of about 5 to 150 ml.
- This viscous diagnostic reagent may then be injected into a subject usually in an amount of .001 to 5 mmole of contrast agent, and the subject may then be imaged by a conventional magnetic resonance imaging system. Typical imaging systems are disclosed, for example; in Scientific American. May 1982, pp.
- N- (glutaramido) desferrioxamine B was prepared similarly using 1.41 g (12.37 mmoles) of glutaric anhydride and 4.91 g (7.47 mmoles) of desferrioxamine B mesylate. Recrystallization from dilute HCl (pH 2.5) gave 3.08 g (4.6 mmoles, 62% of theory) of white solid, mp. 154-158oC.
- Anal. Calc'd for C 30 H 58 N 6 O 11 C, 53.41; H, 8.01; N, 12.46. Found: C, 53.29; H, 7.88; N, 12.37.
- a normal, male Sprague-Dawley rat was anesthetized with 50 mg/kg i.p. sodium pentobarbital and fitted with a tail-vein catheter. The animal was then placed in an imaging coil, and the coil plus animal was inserted into the magnet bore of a General Electric Model CSI-II Iagnetic Resonance Imager/Spectrometer. Non-gated spinecho images were acquired using TR and TE equal to 320 and 15 msec, respectively. Following these pre-contrast images, 0.52 mL of a 0.10 M Fe-PGDF solution was injected, and images were acquired at various time intervals post injection. Within one minute of injection the liver, stomach and small intestine showed enhanced contrast, particularly the small intestine. One hour post injection contrast enhancement of the urinary bladder began with the contrast enhancement of the small intestine being diminished. Several hours post injection showed only enhancement of contrast in the urinary bladder.
- Fe-PGDF 0.25 g (0.31 mmol) was dissolved in 10 mL of anhydrous methanol, and the resulting red solution was treated with 5 mL of a 40% w/w solution of BF 3 in methanol (24 mmol). The solution became purple in color as the BF 3 was added. The reaction mixture was warmed to 60°C for 15 minutes. The methanol then was removed using a rotary evaporator. The residual purple liquid then was treated with aqueous pH 7 buffer, and polystyrene-divinyl benzene beads (e.g., "BioBeads," BioRad, Inc., Hercules, CA). The Fe-PGDF methyl ester was adsorbed onto the beads. Salts and by-products were removed by washing the beads with water. The Fe-PGDF methyl ester was recovered by extraction with methanol. EXAMPLE 9
- DF desferrioxamine
- GDF N-(glutaramido) desferrioxamine
- PSDF N-(phenylsuccinamido)-desferrioxamine
- SDF N-(succinamido)desferrioxamine.
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Abstract
A method is provided utilizing contrast agents which provide increased diagnostic information in the magnetic resonance image of the hepatobiliary system and alimentary tract, especially the small intestine. Novel contrast agents which are N-carboxylated desferrioxamine B complexes with metal ions are provided.
Description
SPECIFIC
CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING OF THE SMALL INTESTINE AND HEPATOBILIARY SYSTEM
This is a continuation-in-part of copending Serial No. 07/205,201, filed June 10, 1988.
The present invention is directed to a novel class of carboxylic acid derivatives of the iron (III) chelate of desferrioxamine B which are useful as magnetic resonance imaging contrast agents for renal, hepatobiliary and, in particular, small intestine image enhancement.
This invention was made with Government support under Grant No. CAa8918 awarded by the Department of Health and Human Services. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
The iron (III) chelate of desferrioxamine B is a known magnetic resonance imaging contrast agent that gives both renal and hepatobiliary enhancement. It is one of the soluble paramagnetic compounds used for this purpose. Other soluble paramagnetic compounds, such as Gd-DTPA, suffer from various disadvantages, such as, rapid diffusion from the vascular system into the extracellular space, lack of specificity for liver and essentially no concentration in the bile. Manganese dichloride concentrates in the liver after IV injection.
is transported to the bile and excreted in the feces. However, it is toxic and is not practically useful in a clinical situation. Iron (III) complexes Fe-EHPG and Fe-HBED are useful contrast agents in the liver and are secreted into the bile. However, their appearance in the bile does not take place until approximately 20 minutes post injection and furthermore, enhancement of the lumen of the small intestine is seldom observed using these agents. The magnetic resonance imaging of the gastrointestinal tract is limited by inherently low image contrast, motion and variable anatomic appearance. Agents for this purpose are normally administered orally and reside within lumen of the GI tract to provide either positive (increased signal strength) or negative (decreased signal strength) contrast. In the usual situation, positive contrast is provided by ingestion of paramagnetic agents .such as Gd-DTPA or iron citrate, while negative contrast is provided by displacement of the luminal proton-containing contents by gas (such as carbon dioxide from gas tablets) or perfluorocarbons. Negative contrast can also be obtained by ingestion of ferromagnetic or superparamagnetic particles, such as ferrite. There is thus a need in the art for MRI contrast agents which are useful both for hepatobiliary studies and for gastrointestinal studies, particularly when introduced by intravenous administration, rather than by oral administration. It is thus an object of the present invention to provide improved desferrioxamine B contrast agents for magnetic resonance imaging.
It is yet another object of the present invention to provide magnetic resonance imaging contrast agents having high stability, low toxicity, physiological tolerability and which provide for positive imaging of the small intestine rapidly after intravenous administration.
It is a further object of the present invention to provide desferrioxamine B contrast agents which are organ selective. SUMMARY OF THE INVENTION
Briefly, these and other objects of the present invention are accomplished by providing chemically stable, physiologically tolerable desferrioxamine B derivatives for in vivo use for MRI imaging. The present invention provides a method for performing magnetic resonance imaging diagnostic procedures in a subject comprising the step of administering intravenously to the subject a magnetic resonance imaging enhancement effective amount of a diagnostic medium comprising the compound of the following formula in a physiologically acceptable carrier:
wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from O to m; s is an integer from 0 to p; p+n+m is less than
or equal to 18; each R1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R2 j, R3 k, R4 k, R7 s and R8 s is independently hydrogen, aryl or substituted aryl as defined above; and R9 is hydroxy, linear or branched alkoxy of 1 to 18 carbon atoms, amino, mono or disubstituted amino, aryloxy or substituted aryloxy as defined above.
BRIEF DESCRIPTION OF THE DRAWING FIGS. 1A through IE are graphs showing the distribution of 59Fe in labelled contrast agents, DF, GDF, PSDF, SDF and PGDF, respectively.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Media according to the present invention are useful for magnetic resonance imaging diagnosis. Production of the diagnostic media according to the present invention may be performed according to ways known in the art, i.e., by forming a complex salt as described hereinbelow, optionally with the addition of customary additives such as galenicals, which may be suspended or dissolved in an aqueous medium followed by sterilization. Suitable additives include, for example, physiologically biocompatible buffers such as tromethamine hydrochloride, complexing agents such as diethylenediiaminepentaacetic acid, or if necessary electrolytes such as sodium chloride.
The compounds according to the present invention which are utilized in the present method are those of the following formula I:
wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from O to m; s is an integer from 0 to p; p+n+m is less than or equal to 18; each R1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R2 j, R3 k, R4 k, R7 s and R8 s is independently hydrogen, aryl or substituted aryl as defined above; and R9 is hydroxy, linear or branched alkoxy of 1 to 18 carbon atoms, amino, mono or disubstituted amino, aryloxy or substituted aryloxy as defined above.
Exemplary aryl groups are phenyl, substituted phenyl, biphenyl, substituted biphenyl, phenanthryl, anthracyl, substituted phenanthryl. A more preferred aryl group or aryloxy group are phenyl and phenoxy and preferably para substituted phenyl or phenoxy.
A second class of complexes are those comprising a metal ion selected from the group consisting of Fe (III),
Dy (III), Gd (III), Cr (III) and Mn (II) and a ligand of the formula (III)
wherein R is -desferrioxamine-B; t and u are integers from 0 to 3 ; R§ is hydroxy or an alkoxy of 1 to 18 carbon atoms or an aryloxy of 6 to 14 carbon atoms, or substituted aryloxy having at least one substituent selected from the group consisting of aryl, nitro, sulfonyl, hydroxl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxy carbonyl of 2 to 6 carbon atoms and sulfhydryl.
Components of the above formula may be made by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of an aromatic dicarboxylic acid, such as phthalic anhydride. By using two or more equivalents of the anhydride to one equivalent of the protected desferrioxamine B, in a basic medium, the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative. Any -O- esters that may have formed during the amidation reaction may. then be removed under conventional conditions to result in the N-carboxylated desferrioxamine B contrast agents according to the present invention. Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C in a suitable solvent,
such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the NOH groups may be protected by esterification or by complexation with a metal ion.
The preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
In the compounds according to the present invention the radical desferrioxamine B is of the following formula II
and is complexed with a paramagnetic ion. The active ingredient of the contrast agents according to the present invention are generally prepared by treating a salt of desferrioxamine B, such as the mesylate, with an appropriate anhydride of a dicarboxylic acid. By using two or more equivalents of the anhydride to one equivalent of the protected desferrioxamine B, in a basic medium, the primary amino group of the desferrioxamine B will react with the anhydride and form an N-carboxylate desferrioxamine B derivative. Any -O- esters that may have formed during the amidation reaction may then be removed under conventional conditions to result in the N-carboxylated; desferrioxamine B contrast agents according to the
present invention. Treatment of the anhydride with desferrioxamine B will normally be conducted at around 100 to 110°C, in a suitable solvent, such as pyridine. Treatment of the ligand with an appropriate metal salt of the desired metal counterion will form the metal complex. Alternatively, the N-OH groups may be protected by esterification or by complexation with a metal ion.
The preferred iron (III) complex of the N-carboxylated desferrioxamine B compound may be prepared by treatment thereof with ferric chloride in an acidic aqueous medium, followed by basification to a pH of about 7.5 to 8.
Particularly preferred contrast agents according to the present invention are the complexes with iron (III) wherein n=1, m=1, p=1, R8, R7, R2, R3 and R3 are hydrogen, X is carbon, R1 is phenyl or substituted phenyl and R9 is hydroxy or methoxy. Preferred ligands are shown in Table 1. In particular, the N-(3-phenylglutaramido) desferrioxamine B iron (III) complex is advantageously used for MRI imaging of the small intestine.
wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from 0 to m; s is an integer from 0 to p; p+n+m is less than or equal to 18; each R1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R2 j, R3 k, R4 k, R7 s and R8 s is independently hydrogen, aryl or substituted aryl as defined above; and R9 is hydroxy, linear or branched alkoxy of 1 to 18 carbon atoms, amino, mono or disubstituted amino, aryloxy or substituted aryloxy as defined above.
The contrast agents according to the present invention are particularly advantageous in that upon intravenous injection, they concentrate in bile, and in some cases, appear in the small intestine very rapidly, usually within about two minutes post injection. They are
useful in that they may be administered by the intravenous route, thus the entry into the small intestine is by the hepatobiliary system. Therefore, in addition to contrast enhancement of alimentary tract lumen, with its resulting increased anatomical information, the contrast agents also provide functional information. For example, hepatobiliary dysfunctions, such as bile duct occlusion will retard, lessen or prevent the transport of the contrast agent and thus be revealed by MRI. Appearance in the intestinal lumen, usually within two minutes post injection, is particularly advantageous for imaging since the optimum imaging time for the small intestine can thereby be readily predicted. Such timing is extremely difficult with use of orally administered agents for MRI of the small intestine. The contrast agents according to the present invention not only show specificity for the biliary system and small intestines, but they also are relatively non-toxic and substantially completely excreted. Conventional hepatobiliary contrast agents, such as Gd-DTPA, distribute in the extracellular volume and are not useful therefore for imaging the small intestine.
The reagents according to the present invention therefore can reveal additional details regarding the anatomy of the small intestines, and because of their very rapid localization in the bile and gut lumen, the MRI of these organ systems are simplified and thereby expedited. It will be appreciated that other metal ions besides iron (III) may be utilized to complex with the ligands according to the present invention for use in magnetic resonance imaging. Useful metal ions include Dy (III), Gd (III), Cr (III), and Mn (II).
The agents according to the present invention are utilized preferably in solutions made by addition of a solvent such as water, serum, albumin solutions, or saline to the complex. A typical injectable composition will contain about 10 mg/ml human serum albumin with a metal complex concentration of about 20 to 200 mg/ml. A 0.1 m phosphate buffer (7.5 pH) may be employed containing, for example, about 0.9% sodium chloride. The pH of the aqueous solutions may range between about 5 to 9 over a volume range of about 5 to 150 ml. This viscous diagnostic reagent may then be injected into a subject usually in an amount of .001 to 5 mmole of contrast agent, and the subject may then be imaged by a conventional magnetic resonance imaging system. Typical imaging systems are disclosed, for example; in Scientific American. May 1982, pp. 78-88, and "NMR: A Primer For Medical Imaging" by Wolf and Popp, Slack Book Division (ISBN 0-943432-19-7), which are incorporated herein by reference. The following examples are provided by way of illustration of the invention but are not in any way intended to limit the invention.
EXAMPLE 1
Preparation of 3-Phenylglutaric Anhydride
3-Phenylglutaric anhydride, 5.0 g (24 mmoles), was dissolved in 25 ml of dry acetic anhydride, and the resulting solution was heated to 100°C and stirred for 3 hours. The reaction mixture then was allowed to cool to 35°C and held at that temperature for 1.5 hours. Removal of the acetic anhydride using a rotary evaporator, and recrystallization of the resulting crude solid from chloroform gave 2.25 g (11.8 mmoles; 50% of theory) of the title compound, mp. 102-103ºC.
EXAMPLE 2
Preparation of N-(-phenylglutaramidol desferrioxamine To 1.5 g (2.28 mmoles) of desferrioxamine B mesylate in 30 mL of pyridine was added 0.85 g (4.47 mmoles) of 3-phenylglutaric anhydride. The resulting solution was stirred for 2 hours at 110ºC, cooled to 55ºC, and then held at that temperature for 18 hours. Then 30 ml of 2 N aqueous ammonia was added to the reaction mixture, and it was stirred for 15 minutes at ambient temperature. Pyridine was removed from the reaction mixture by extraction with dichloromethane. The aqueous fraction then was striped to dryness using a rotary evaporator. The resulting solid residue was redissolved in 40 ml of water, and this solution was acidified to pH 2-2.5 by the addition of 1 N HCl. After acidification, the solution was filtered, and the filtrate was treated with an equivalent volume of acetone. Cooling of this solution afforded 1.29 g (1.72 mmoles; 75% of theory) of white solid, mp. 123.5-126°C. Anal. Calc'd for C36H58N6O11:C, 57.60; H, 7.73; N, 11.20. Found: C, 57.39; H, 7.59; N, 11.2. Mass spectrum (LSIMS) : (M+H)+=751; (M+Na)+=773.
EXAMPLE 3
Preparation of N-(Glutaramido)desferrioxamine B
N- (glutaramido) desferrioxamine B was prepared similarly using 1.41 g (12.37 mmoles) of glutaric anhydride and 4.91 g (7.47 mmoles) of desferrioxamine B mesylate. Recrystallization from dilute HCl (pH 2.5) gave 3.08 g (4.6 mmoles, 62% of theory) of white solid, mp. 154-158ºC. Anal. Calc'd for C30H58N6O11: C, 53.41; H, 8.01; N, 12.46. Found: C, 53.29; H, 7.88; N, 12.37. Mass spectrum (LSIMS): (M+H)+=675; (M+Na)+=697.
EXAMPLE 4
Synthesis of N-(succinaτnido) desferrioxamine B
N-(succinamido)desferrioxamine B was prepared similarly to the glutaric derivative using 0.68 g (6.8 mmoles) of succinic anhydride and 2.0 g (3.0 mmoles) of desferrioxamine B mesylate. Recrystallization from dilute HCl (pH 2.5) gave 0.72 g (1.1 mmoles, 37% of theory) of white solid, mp. 152-154°C. Anal. Calc'd for C29H52N6O11: C, 52.71; H, 7.93; N, 12.72. Found: C, 52.5; H, 7.9; N, 12.4. Mass spectrum (LSIMS): (M+H)+=661; (M+Na)+=683.
EXAMPLE 5
Preparation of the Fe(III) Complex of N-(3-phenylglutaramido)desferrioxamine (Fe-PGDF)
To 160 mg (12 mmoles) of imidoacetic acid dissolved in 1 ml of aqueous NaOH (pH=8), was added 134 mg (5 mmoles) of FeCl3 6 H2O. This solution was brought to pH=8 with 2N NaOH, and to it was added 375 mg (5 mmoles) of N-(3-phenylglutaramido)desferrioxamine (PGDF) dissolved in 1 mL of water. The resulting mixture was adjusted to pH-7.5 with 2N NaOH, and filtered through a 0.2 um filter to yield a red solution of the Fe(III) complex. After appropriate dilution with water, this material was used for in vivo imaging experiments. Similar Fe(III) complexes were prepared using the ligands made in Examples 3 and 4.
EXAMPLE 6
A normal, male Sprague-Dawley rat was anesthetized with 50 mg/kg i.p. sodium pentobarbital and fitted with a tail-vein catheter. The animal was then placed in an imaging coil, and the coil plus animal was inserted into the magnet bore of a General Electric Model CSI-II Iagnetic Resonance Imager/Spectrometer. Non-gated spinecho images were acquired using TR and TE equal to 320 and 15 msec, respectively. Following these pre-contrast
images, 0.52 mL of a 0.10 M Fe-PGDF solution was injected, and images were acquired at various time intervals post injection. Within one minute of injection the liver, stomach and small intestine showed enhanced contrast, particularly the small intestine. One hour post injection contrast enhancement of the urinary bladder began with the contrast enhancement of the small intestine being diminished. Several hours post injection showed only enhancement of contrast in the urinary bladder.
EXAMPLE 7
Using the basic procedure of Examples 1, 2 and 5, Fe (III) complexes were prepared except that 3-phenylglutaric anhydride was replaced . by, respectively, p-chlorophenylglutaric anhydride, p-isopropylphenylglutaric anhydride, p-t-butylphenyl glutaric anhydride, p-nitrophenylglutaric anhydride, p-trichloromethylphenylglutaric anhydride, andphthalic anhydride. EXAMPLE 8
Fe-PGDF, 0.25 g (0.31 mmol) was dissolved in 10 mL of anhydrous methanol, and the resulting red solution was treated with 5 mL of a 40% w/w solution of BF3 in methanol (24 mmol). The solution became purple in color as the BF3 was added. The reaction mixture was warmed to 60°C for 15 minutes. The methanol then was removed using a rotary evaporator. The residual purple liquid then was treated with aqueous pH 7 buffer, and polystyrene-divinyl benzene beads (e.g., "BioBeads," BioRad, Inc., Hercules, CA). The Fe-PGDF methyl ester was adsorbed onto the beads. Salts and by-products were removed by washing the beads with water. The Fe-PGDF methyl ester was recovered by extraction with methanol.
EXAMPLE 9
A solution of p-NO2-PGDF (1.5 g 0.188 mmol) in methanol
(25 mL) along with 10% Palladium-on-carbon catalyst
(0.10 g) was placed under a hydrogen atmosphere (1 atmosphere pressure). After being stirred for five hours at 25ºC, the reaction mixture was filtered to remove the catalyst. The resulting filtrate was concentrated under reduced pressure to a volume of 1-2 mL. Upon cooling to -20ºC, p-NH2-PGDF was isolated as a white solid, 0.117 g (0.155 mmol).
EXAMPLE 10
The distribution of 59Fe in the whole body, urine and feces of rats was followed for seven days after i.v. bolus doses of 59Fe-labelled substituted ferriόxamine contrast agents. The results are shown in FIGS. 1A-1E. DF=desferrioxamine; GDF=N-(glutaramido) desferrioxamine; PSDF=N-(phenylsuccinamido)-desferrioxamine; SDF=N-(succinamido)desferrioxamine. Each animal and its excreta were counted at selected time points for seven days following injection. For 59Fe-DF, 59Fe-SDF, and 59-Fe-GDF, nearly all of the dose was excreted in the urine within the first day. With the addition of a phenyl group (i.e., 59Fe-PSDF and 59Fe-PGDF), nearly half of the total radiolabel appeared in the feces, demonstrating hepatobiliary elimination. In all cases, little of the injected 59Fe remained in the body at 7 days. Data are means plus standard deviations (n=3,4).
Claims
1. A metal complex comprising a metal ion selected from the group consisting of Fe(III), Dy(III), Gd(III), Cr(III) and Mn(II) and a ligand of the formula
2. A metal complex according to Claim 1 wherein R is
and said metal is iron (III).
3. A complex according to Claim 2 wherein n=1, m=1 and p=1; R9 is hydroxy; X is carbon; R8, R7, R2, R3 and
R4 are all hydrogen and R1 is phenyl or substituted phenyl.
4. A complex according to Claim 2 wherein p=1, n=1 and m=1; R2, R3, R4, R7, and R8 are all hydrogen, R9 is methoxy; X is carbon and R1 is phenyl or substituted phenyl.
5. A complex according to Claim 3 wherein R1 is p-chlorophenyl.
6. A complex according to Claim 3 wherein R1 is p-i-propylphenyl.
7. A complex according to Claim 3 wherein R1 is p-t-butyl-phenyl.
8. A complex according to Claim 3 wherein R1 is p-nitro-phenyl.
9. A complex according to Claim 3 wherein R1 is p-amino-phenyl.
10. A complex according to Claim 3 wherein R1 is p-(trifluoromethyl)-phenyl.
11. A complex according to Claim 4 wherein R1 is p-chloro-phenyl.
12. A complex according to Claim 4 wherein R1 is p-i-propyl-phenyl.
13. A complex according to Claim 4 wherein R1 is p-t-butyl-phenyl.
14. A complex according to Claim 4 wherein R1 is p-nitro-phenyl.
15. A complex according to Claim 4 wherein R1 is p-amino-phenyl.
16. A complex according to Claim 4 wherein R1 is p-(trifluoromethyl)-phenyl.
17. A complex according to Claim 2 wherein n=1, m=0, and p=1; R8, R7, and R2 are all hydrogen; R9 is hydroxy, and R1 is phenyl or substituted phenyl.
18. A complex according to Claim 2 wherein n=1, m=1, and p=0; R3, R4, and R2 are all hydrogen; R9 is hydroxy, and R1 is phenyl or substituted phenyl.
19. A complex according to Claim 17 wherein R1 is p-chloro-phenyl.
20. A complex according to Claim 17 wherein R1 is p-i-propyl-phenyl.
21. A complex according to Claim 17 wherein R1 is p-t-butyl-phenyl.
22. A complex according to Claim 17 wherein R1 is p-nitro-phenyl.
23. A complex according to Claim 17 wherein R1 is p-amino-phenyl.
24. A complex according to Claim 17 wherein R1 is p-(trifluoromethyl)-phenyl.
25. A complex according to Claim 2 wherein n=1, m=0, p=1; R1 is methoxy; R8, R7 and R2 are all hydrogen; and R1 is phenyl or substituted phenyl.
26. A complex according to Claim 25 wherein R1 is p-chlorophenyl.
27. A complex according to Claim 25 wherein R1 is p-i-propyl-phenyl.
28. A complex according to Claim 25 wherein R1 is p-t-butyl-phenyl.
29. A complex according to Claim 25 wherein R1 is p-nitro-phenyl.
30. A complex according to Claim 25 wherein R1 is p-amino-phenyl.
31. A complex according to Claim 25 wherein R1 is p-(trifluoromethyl)-phenyl.
32. A complex according to Claim 18 wherein R1 is p-chloro-phenyl.
33. A complex according to Claim 18 wherein R1 is p-i-propyl-phenyl.
34. A complex according to Claim 18 wherein R1 is p-t-butyl-phenyl.
35. A complex according to Claim 18 wherein R1 is p-nitro-phenyl.
36. A complex according to Claim 18 wherein R1 is p-amino-phenyl.
37. A complex according to Claim 18 wherein R1 is p-(trifluoromethyl)-phenyl.
38. A complex according to Claim 2 wherein n=1, m=1, p=0; R8, R7, and R2 are all hydrogen; R9 is methoxy and R1 is phenyl or substituted phenyl.
39. A complex according to Claim 38 wherein R1 is p-chlorophenyl.
40. A complex according to Claim 38 wherein R1 is p-i-propyl-phenyl.
41. A complex according to Claim 38 wherein R1 is p-t-butyl-phenyl.
42. A complex according to Claim 38 wherein R1 is p-nitro-phenyl.
43. A complex according to Claim 38 wherein R1 is p-amino-phenyl.
44. A complex according to Claim 38 wherein R1 is p- (trifluoromethyl)-phenyl.
45. A complex according to Claim 2 wherein X is nitrogen; n=1, m=1, p=1; R9 is hydroxy; R8, R7, R2, R3 and R4 are all hydrogen and R1 is phenyl or substituted phenyl.
46. A complex according to Claim 2 wherein X is nitrogen, p=1, n=1, m=1; R2, R3, R4, R7 and R8 are all hydrogen; R9 is methoxy and R1 is phenyl or substituted phenyl.
47. A metal complex comprising a metal ion selected from the group consisting of Fe(III), Dy(III), Gd(III), Cr(III) and Mn(II) and a ligand of the formula
wherein R is -desferrioxamine B; t and u are integers from 0 to 3; E, is hydroxy, an alkoxy of 1 to 18 carbon atoms or anryloxy of 6 to 14 carbon atoms, or substituted aryloxy having at least one substituent selected from the group consisting of halo, nitro, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl.
48. A complex according to Claim 47 wherein R is
49. A complex according to Claim 48 wherein R9 is hydroxy and t=u=0.
50. A complex according to Claim 48 wherein R9 is methoxy and t=u=0.
51. A complex according to. Claim 48 wherein R9 is hydroxy and t=u=1.
52. A complex according to Claim 48 wherein R9 is methoxy and t=u=1.
53. A compound of the formula
wherein X is carbon or nitrogen; R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from O to m; s is an integer from 0 to p; p+n+m is less than or equal to 18; each R1 j is independently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms; alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy or 1 to 6 carbon atoms, carboalkoxy to 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R2 j, R3 k, R4 k, R7 s and R8 s is independently hydrogen, aryl or substituted aryl as defined above; and R9 is hydroxy, linear or branched alkoxy of 1 to 18 carbon atoms, amino, mono- or di-substituted amino; aryloxy or substituted aryloxy as defined above.
54. A compound according to Claim 53 wherein R is
55. A compound according to Claim 54 wherein n=1, m=1 and p=1; R9 is hydroxy; X is carbon; R8, R7, R2, R3 and R4 are all hydrogen and R1 is phenyl or substituted phenyl.
56. A compound according to Claim 54 wherein p=1, n=1 and m=1; R2, R3, R4, R7 and R8 are all hydrogen; R9 is methoxy; X is carbon and R1 is phenyl or substituted phenyl.
57. A method of performing a magnetic resonance imaging diagnostic procedure on a subject comprising the step of administering to said subject a magnetic resonance image enhancing amount of a diagnostic medium, and then measuring a magnetic resonance image of at least a portion of said subject's body, wherein said diagnostic medium comprises a physiologically compatible complex according to any of claims 1 to 52 and 61-59.
58. A method according to Claim 57 wherein said portion of said subject's body subjected to magnetic resonance imaging comprises the kidneys.
59. A method according to Claim 57 wherein said portion of said subject's body subjected to magnetic resonance imaging comprises the hepatobiliary system.
60. The method according to Claim 57 wherein said portion of said subject's body subjected to magnetic resonance imaging comprises the small intestinal lumen.
61. A metal complex comprising a metal ion selected from the group consisting of Fe(III), Dy(III), Gd(III), Cr(IIl) and Mn(II) and a ligand of the formula:
wherein R is -desferrioxamine B; j is an integer from 1 to n; k is an integer from 0 to m; s is an integer from O to p; p+n+m is less than or equal to 18; each R1 j is indpendently aryl of 6 to 14 carbon atoms, or substituted aryl having at least one substituent selected from the group consisting of halo, haloalkyl of 1 to 6 carbon atoms and 1 to 13 halo atoms, alkyl of 1 to 6 carbon atoms, nitro, amino, sulfonyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms and sulfhydryl; and each R2 j, R3 k, R4 k, R7 s and R8 s is independently hydrogen, aryl or substituted aryl as defined above; and R9 is hydroxy, linear or branched alkoxy of 1 to 18 carbon atoms, amino, mono or disubstituted amino, aryloxy or substituted aryloxy as defined above.
62. A metal complex according to Claim 61 wherein R is
and said metal is iron (III).
63. A complex according to Claim 62 wherein n=1, m=1 and p=1; R9 is hydroxy; R8, R7, R2, R3 and R4 are all hydrogen and R1 is phenyl or substituted phenyl.
64. A complex according to Claim 62 wherein p=1, n=1 and m=1; R2, R3, R4, R7 and R8 are all hydrogen, R9 is methoxy; and R1 is phenyl or substituted phenyl.
65. A complex according to Claim 63 wherein R1 is p-chlorophenyl.
66. A complex according to Claim 63 wherein R1 is p-i-propylphenyl.
67. A complex according to Claim 63 wherein R1 is p-t-butyl-phenyl.
68. A complex according to Claim 63 wherein R1 is p-nitro-phenyl.
69. A complex according to Claim 63 wherein R1 is p-anino-phenyl.
70. A complex according to Claim 63 wherein R1 is p- (trifluoromethyl)-phenyl.
71. A complex according to Claim 64 wherein R1 is p-chloro-phenyl.
72. A complex according to Claim 64 wherein R1 is p-i-propyl-phenyl.
73. A complex according to Claim 64 wherein R1 is p-t-butyl-phenyl.
74. A complex according to Claim 64 wherein R1 is p-nitro-phenyl.
75. A complex according to Claim 64 wherein R1 is p-amino-phenyl.
76. A complex according to Claim 64 wherein R1 is p-(trifluoromethyl)-phenyl.
77. A complex according to Claim 62 wherein n=1, m=0 and p=1; R8, R7 and R2 are all hydrogen, R9 is hydroxy and R1 is phenyl or substituted phenyl.
78. The complex of Claim 77 wherein substituted phenyl is independently selected from p-chloro-phenyl, p-i-propylphenyl, p-t-butyl-phenyl, p-nitro-phenyl, p-amino-phenyl, or p-(trifluoromethyl)-phenyl.
79. A complex according to Claim 62 wherein n=1, m=1 and p=0; R3, R4 and R2 are all hydrogen, R9 is hydroxy and R1 is phenyl or substituted phenyl.
80. The complex of Claim 79 wherein substituted phenyl. is independently selected from p-chloro-phenyl, p-i-propylphenyl, p-t-butyl-phenyl, p-nitro-phenyl, p-amino-phenyl, or p-(trifluoromethyl)-phenyl.
81. A complex according to Claim 62 wherein n=1, m=0 and p=1; R9 is methoxy; R8, R7 and R2 are all hydrogen; and R1 is phenyl or substituted phenyl.
82. The complex of Claim 81 wherein substituted phenyl is independently selected from p-chloro-phenyl, p-i-propylphenyl, p-t-butyl-phenyl, p-nitro-phenyl, p-amino-phenyl, or p-(trifluoromethyl)-phenyl.
83. A complex according to Claim 81 wherein R1 is p-amino-phenyl.
84. A metal complex comprising a metal ion selected from the group consisting of Fe(III), Dy(III), Gd(III), Cr(III) and Mn(II) and a ligand of the formula:
85. A metal complex according to Claim 84 wherein R is
and said metal is iron (III).
86. The metal complex of Claim 85 wherein n=1, m=1, p=1; R9 is selected from linear or branched alkoxy having 3 to 10 carbon atoms.
87. The metal complex of Claim 85 wherein Rg is independently selected from amino, mono or disubstituted amino, aryloxy or substituted aryloxy as defined above.
88. The metal complex of Claim 2, wherein X is carbon, with the proviso that when R9 is methoxy, R1 is substituted phenyl.
89. The metal complex of Claim 3, wherein X is carbon, with the proviso that when R9 is hydroxyl, R1 is a substituted phenyl selected from p-amino-phenyl or p-(trifluoromethyl)-phenyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1992/000678 WO1993015093A1 (en) | 1992-01-29 | 1992-01-29 | Specific contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1992/000678 WO1993015093A1 (en) | 1992-01-29 | 1992-01-29 | Specific contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993015093A1 true WO1993015093A1 (en) | 1993-08-05 |
Family
ID=22230757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1992/000678 WO1993015093A1 (en) | 1992-01-29 | 1992-01-29 | Specific contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1993015093A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049326A1 (en) * | 1999-12-29 | 2001-07-12 | Bracco Imaging S.P.A | Use of contrast agents in the manufacture of diagnostic agent for the visualisation of the intestinal lumen |
| WO2009055863A1 (en) * | 2007-11-01 | 2009-05-07 | The University Of Sydney | Desferrioxamine conjugates, derivatives and analogues |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758422A (en) * | 1985-01-04 | 1988-07-19 | Salutar Inc. | Ferrioxamine paramagnetic contrast agents for MR imaging |
| US4999445A (en) * | 1988-06-10 | 1991-03-12 | The Regents Of The University Of California | Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system |
-
1992
- 1992-01-29 WO PCT/US1992/000678 patent/WO1993015093A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758422A (en) * | 1985-01-04 | 1988-07-19 | Salutar Inc. | Ferrioxamine paramagnetic contrast agents for MR imaging |
| US4999445A (en) * | 1988-06-10 | 1991-03-12 | The Regents Of The University Of California | Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049326A1 (en) * | 1999-12-29 | 2001-07-12 | Bracco Imaging S.P.A | Use of contrast agents in the manufacture of diagnostic agent for the visualisation of the intestinal lumen |
| JP2003519200A (en) * | 1999-12-29 | 2003-06-17 | ブラッコ イメージング エッセ ピ ア | Use of contrast agents in the manufacture of diagnostic agents for intestinal lumen visualization |
| CN1302814C (en) * | 1999-12-29 | 2007-03-07 | 布雷克成像有限公司 | Use of contrast agents in manufacture of diagnostic agent for visualisation of intestinal lumen |
| JP4798919B2 (en) * | 1999-12-29 | 2011-10-19 | ブラッコ イメージング エッセ ピ ア | Use of contrast agents in the manufacture of diagnostic agents for intestinal lumen visualization |
| WO2009055863A1 (en) * | 2007-11-01 | 2009-05-07 | The University Of Sydney | Desferrioxamine conjugates, derivatives and analogues |
| US8309583B2 (en) | 2007-11-01 | 2012-11-13 | Rachel Codd | Desferrioxamine conjugates, derivatives and analogues |
| AU2008318287B2 (en) * | 2007-11-01 | 2013-01-17 | The University Of Sydney | Desferrioxamine conjugates, derivatives and analogues |
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