IE66460B1 - 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes their methods of preparation and X-ray contrast media containing them - Google Patents
1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes their methods of preparation and X-ray contrast media containing themInfo
- Publication number
- IE66460B1 IE66460B1 IE398691A IE398691A IE66460B1 IE 66460 B1 IE66460 B1 IE 66460B1 IE 398691 A IE398691 A IE 398691A IE 398691 A IE398691 A IE 398691A IE 66460 B1 IE66460 B1 IE 66460B1
- Authority
- IE
- Ireland
- Prior art keywords
- hydroxy
- amino
- bis
- aminocarbonyl
- propane
- Prior art date
Links
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 15
- 239000002872 contrast media Substances 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 46
- 125000002768 hydroxyalkyl group Chemical group 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940039231 contrast media Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 77
- -1 2,3-dihydroxy-propyl Chemical group 0.000 claims description 49
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 45
- 239000001294 propane Substances 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 238000009833 condensation Methods 0.000 claims description 10
- 230000005494 condensation Effects 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- SKCKOFZKJLZSFA-KVTDHHQDSA-N (2r,3r,4r,5r)-hexane-1,2,3,4,5-pentol Chemical compound C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SKCKOFZKJLZSFA-KVTDHHQDSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 235000013350 formula milk Nutrition 0.000 claims 16
- 239000001257 hydrogen Substances 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 239000012670 alkaline solution Substances 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 112
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 29
- 238000000921 elemental analysis Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 20
- 229910001868 water Inorganic materials 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229940086542 triethylamine Drugs 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 7
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000003456 ion exchange resin Substances 0.000 description 6
- 229920003303 ion-exchange polymer Polymers 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- UYBWIEGTWASWSR-UHFFFAOYSA-N 1,3-diaminopropan-2-ol Chemical compound NCC(O)CN UYBWIEGTWASWSR-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 3
- DWQBWQNQEGJFKV-UHFFFAOYSA-N 3-carbamoyl-2,4,6-triiodobenzoyl chloride Chemical compound NC(=O)C1=C(I)C=C(I)C(C(Cl)=O)=C1I DWQBWQNQEGJFKV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 238000009608 myelography Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 241000894007 species Species 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- HXOYWCSTHVTLOW-UHFFFAOYSA-N (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine Chemical compound CC1(C)OCC(CN)O1 HXOYWCSTHVTLOW-UHFFFAOYSA-N 0.000 description 1
- CIAMOALLBVRDDK-UHFFFAOYSA-N 1,1-diaminopropan-2-ol Chemical compound CC(O)C(N)N CIAMOALLBVRDDK-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- FQRLLDVTIIHZGX-UHFFFAOYSA-N 1,3-dioxan-2-amine Chemical compound NC1OCCCO1 FQRLLDVTIIHZGX-UHFFFAOYSA-N 0.000 description 1
- AKUNSTOMHUXJOZ-UHFFFAOYSA-N 1-hydroperoxybutane Chemical compound CCCCOO AKUNSTOMHUXJOZ-UHFFFAOYSA-N 0.000 description 1
- CRVYPNHLIAWRNV-UHFFFAOYSA-N 2,4,6-triiodobenzoic acid Chemical class OC(=O)C1=C(I)C=C(I)C=C1I CRVYPNHLIAWRNV-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 241000212977 Andira Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
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- 206010028813 Nausea Diseases 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000000576 arachnoid Anatomy 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 159000000007 calcium salts Chemical class 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- MNRGFUBMMILKAL-UHFFFAOYSA-N methyl phenylmethanesulfonate Chemical compound COS(=O)(=O)CC1=CC=CC=C1 MNRGFUBMMILKAL-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
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- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
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- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000007487 urography Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Symmetrical or asymmetrical 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or polyhydroxyalkyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes, useful to constitute the opacifying component of X-ray contrast media, are described.
Description
This invention relates to symmetrical or asymmetrical 1,3-bis-[3~(mono- or po ly-hydroxy )acylamino-5(mono- or polyhydroxvalkyl)aminocarbonyl-2,4,6-trxiodobenzoyl-amino] -hydroxy- or hydroxyalkyl-propanes, use5 . ful to constitute the opacifying component of X-ray contrast media, of general formula (I) A B * wherein: R, R, which are the same or different, are a straight or branched mono- or poly-hydroxyalkyl C1-Cg residue containing from 1 to 2 OH groups, Κ'Ί, R9, Rg, which are the same or different, are H or 20 Cn3, Rj, {, Rgij? Rgt, which are the same or different, are H or CEL J r t * Alkyl (OH) is one of the groups of formula -CHCCH2OH5CH(OH)CH9OH, -CH(CH2OH)2, -CH2CB(OH)25 CB'2GH, -CH2(CHOE)4CH,OH, or -CH,CB2OE, 6 4 6 Ο X is one of the - groups -CH(OH)-, -GB(CH2OH)-, -C(OH)(CH2OB>- or ~C(CH90H)2-, A and S, may be the same.or different» The invention also comprises the possible enantio5 mers, diastereoisomers and/or rotamers of compounds (I?The invention also relates to a process for the preparation of these non-ionic compounds, as well as to the X-ray contrast media which contain them as opa10 drying components» Preferred compounds of formula (I) are the ones in which R«, R3, Rj’,» are H. Particularly preferred are the ones in which X represents the -CH(OH)- group» Prom the structural point of view, the non-ionic X-ray' contrast agents which are more similar to the ones of this invention are the a,^bis"[3-hydroxyacyl&mino~5C dihydroxyalkyl} aminocarbony 1-2,41,6-triiodo-benzoylamino)~oxaalkanes described in patents DE 2805928 and OS 4,139,505. In these compounds the two' triiodo-ben20 soyl-arain© residues are joined via an oxaalkylenie residue of formula ). - contain zn n zn o—4 n rn ning from 4 to 12 atoms of c and from 1 to 5 atoms of 0» They can produce oversaturated solutions and after some time, these ones may spontaneously crystallize, therefore causing a limitation to the use of such compounds. Patent OS 4,062,934 describes N,N-bis-(3-Kraethyl"N-acetylamino~5~N-gluconylamino~2,4,6-triiodobenzoyl)-diaminoalkanes. Due to an iodine content comparatively low, they show a reduced opacifying capa30 city. In addition, their solutions are quite viscous. These features cause some problems when the product is used in procedures which require administration via catheter.
N,N’-bis-{3~acyiamino-5~N~methyl-carbamoyl-2,4,6triiodo-bensoyl-amino)-carboxyalkanes are described in patent application GB 1,488,904. The preparation ox solutions acceptable from the pharmacological point of view requires that free carboxylic groups, where present, are neutralised. Therefore, if compared to the non-ionic contrast agents, the solutions of the com10 pounds described in the above mentioned patent application have a high osmolality. Similarly, their neurotoxicity is higher than the one-of the non-ionic contrast mediaSovak et Al. described in application WO 8501727, among other compounds, also N,N’J-bis-[3,5.-bis~(N-2,3dihy droxy-propyl-N-acetyl amino )-2,4 ·, S-triiodo-bensoyl J ethylendiamines and th© corresponding N’-hydroxyalkylderivatives. The synthesis of these compounds is quite difficult- The four 2,3-dihydroxy-propyl groups are ob20 tained by treating the corresponding tetraalkenylderivatives with 1-butyl-hydroperoxide in the presence of osmium tetroxide- The reaction occurs in a fragmented and unaccomplished way. None of the compounds described, mentioned or claimed by Sovak has as' conjunction bridge of the two 2,4,6-triiodo-benzoyl-amino residues the hydroxyalkyXenie chain of formula -ca^-X-CH^-*, with X equivalent to ~CE{OH}-, -CS(CH^OB)-, -C(OE)(CS^OH)or which is characteristic of this invention. ··.
A last reference concerns the European patent applications EP 74307 and E? 74309 abandoned in, 1985« The first one only . describes aromatic bi- or tricyclic compounds where the aromatic moiety contains iodine and bromine atoms at the same time and in the same molecule5 The second one does not describe new compounds, but a process which' increases the tolerability of opacifying compositions by using a mixture of xodoben.zen.ic and bromobenzenic compounds- The general formulas describing these compounds are extremely wide, unclear and indefinite and include billions of compounds basically different among them.
The compounds of formula (I) belong to the class of non-ionic contrast agents for X-ray diagnosis, which are more and more replacing the salts up to now used of the derivatives of 2,4,6-triiodo-benzoic acid, due to their better tolerability and the reduced side-effectsThanks to the elimination of the ionic species, their solutions, if compared to the ones of the ionic agents, have the same content of iodine, but a lower osmotic pressure, that’s to say a lower osmolality- Therefore, for instance, in angiography, they cause less pain and endothelial damage. In subarachnoidal administration for myelography and cisternography, unlike the previously used contrast media, they rarely cause arachnoid!25 tis or epileptic disorders. Unfortunately non-ionic contrast agents, consisting of iodinated monocyclic aromatic nuclei, are still too hypertonic, despite their excellent physical and pharmacological properties, if compared with blood, at the high .dosages and high concentrations which many diagnoses require. This fact led to the development of bicyclic hexaiodinated compounds, whose osmolality is reduced in comparison with the total amount of iodine in the molecule., However, concentrated solutions of these compounds are frequently too much' viscous» In addition, a large number of products, even if they are expected to be promising from the theoretical point of view, are not enough soluble.
For this reason, researchers investigated on new hexaiodinated bicyclic derivatives characterized by: high solubility, low viscosity and osmolality as well as high intravenous, intracisternal and ·intracerebral tolerability and minimum tendency to give side affects (pain, temperature increase, nausea, decrease of pressure and vessel damages)» In particular, physicians need new contrast media characterized by a wide range of possible uses, i.e- .in urography, angiography, cardioangiography, flebography, myelography, cisternography, lymphography, isterosalpingography, bronchography and gastrography or the visualisation of articular cavities.» The products of this invention are generally characterised by a good water solubility, which can exceed X00 g per 100 ml of solution at 20*0, and a low toxicity.
If compared to the known hexaiodinated dimers, they show low osmolality without causing' a foreseeable corresponding rise in the viscosity.
One of the preferred compounds of the invention is for example l,3-bis-[3-(Ir-2-hydroxy-px0pionyl)amino-5(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,S-triiodobenzoyl-amino]-2-hydroxy-propane (compound A of Table 2). Xt gives-stable aqueous solutions which contain, at 20°C, more than 100 g of product in 100 ml of solution.
' As far as the physiological characteristics are concerned, the study of plasma kinetics' revealed half life for the distribution and elimination phases of 2.9 and 22.9 min, after intravenous administration in rats (200 mgl/kg).
The apparent volume of distribution is 123.5 ml/kg showing that the product is distributed in plasma and the extracellular spaces. The total clearance is 7.9 ml .-1,-1 . am *. kg Elimination occurs mainly through urinary pathway and in less extent through the bile. After 7 hours from the administration, 76-7% of the administered dose was found in the urine and 3.5% in the bile.
Its tolerability' is very good as reported in Table 1.
In Table 2, there are reported the values.of some charseteristic properties of preferred products of this invention in comparison with XODXXANOL (Nycomed), which is an hexaiodinated non-ionic dimer ia advanced phase of development (EP 108633; CLINICA 413, p 7, 08.08.90).
The process for the preparation of -the l,3-bis-[3(mono- or poly-hydroxy) acylamino-5-(mono- or poly-hydroxyalkyl )aminocarbonyl-2,4,6-triiodo-benzoyl-aminoIhydroxy- or hydroxyalkyl-propanes of general formula (I) is characterized ia that a 1,3-diamino-hvdroxy- or hydroxyalkyl-propane of general formula (II) R3-HN-CH,-X-CH,-NH-R3’ cIX > wherein R3 and R3’ are H or CH3, is one of the groups -CH(OH)-, ~CH(CB2OB)-, -C(OB) (CP^OH)- or -C(CH^OH)2" and one of the amino groups may be protected by a suitable protective group, is reacted, directly or by a multi-step process, with a reactive derivative of a 3-(mono- or poly-acyloxy)aclyamino-5-(monoor poly-hydroxyalkyl) aminocarbonyl-2,4,6-triiodo-benzoxc acid of general formula (III) wherein: R1, R2, are H or CH^, R^, is a straight or branched mono- or poly-acyloxyalkyl C^-C13 residue containing from .3 to 13 atoms of c and from 1 to 2 lower acyloxy groups C’2~C5, Alkyl(OH)Ί_5, is one of the groups of formula -CE2CH(OH)ce2OB, -CB2CH2OH, -CBCCHjOHij, ~CH(CH,OH)CH(OB3CH,OB or -CH2(CBOH)4CE2OB, where the hydroxy groups may be preferably protected by acetalic or ketslic groups.
CO-T, xS the residue of a mixed anhydride or, preferably, a halocarbonyl group, to give a compound of general formula £.IV) wherein R^, R^, R^, R1 ’ R^·, R-j’, R4, Alkyl (OH and X have the meaning as previously defined and R^ may he R or Rz, preferably according to one of the two following procedures: a) a compound of formula (II) is reacted with a compound of formula (III) in a. molar ratio of 1:2 In a solvent . and In the presence of a basic condensation agent in order to obtain the corresponding compound of formula (IV) where Rg corresponds to R^# b) a compound of· formula (II), where -one of the two amino groups Is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent in order to obtain, after hydrolysis of the protective groups, the corresponding l-[ 3-(mono- or poly-hydroxy)acy lamino-5- (mono- or poly-hydroxyalkyl) aminocarbony1-2,4,δ-triiodo-benzoyl-amino3-3-aminohydroxyalkyl derivative of general formula (V) NH 00. wherein R, R^, R9, Rg, R3', Alkyl(OH)Ί_5 and X have the meaning as previously defined, and this compound (V) is subsequently reacted with a derivative of formula (III) in the presence of a basic condensation agent to obtain compound (IV) where R^ is R, then, the compound of formula (IV), obtained by synthetic methods a). or b), is transformed by hydrolysis of the protective groups, into the corresponding compound of formula (I). Finally, in case that ΚΊ, Rj are H, this last one may, if desidered, be methylated in alkaline medium.
Methylation occurs through reaction with suitable methylating agents, for .instance methyl halides, dime thyXsulphate, methylsulphonate, dime thy Icarbonate. For instance, the di-sodium derivative of general formula (VI) is prepared in a basic environment, preferably in the presence of alcoholate or .alkaline hydroxide, and is then transformed into the corresponding dimethyl derivative of general formula (VII) evil). by treatment with methyl halides, dimethylsulphate, dimethyl carbonate, methyl methanesulphonate, methyl benzenesulphonate, methyl toluenesulphonate.
In case of direct reaction of the product of gene5 ral formula (II) with a compound of general formula (III), according to synthesis a), symmetrical products are obtained, where both residues A and 3 of general formula (I) are identical.
Following the multistep reaction according to 10 synthesis b), asymmetrical products may be obtained, in which the residues A and B of general formula (I) are different. In.fact, during the second step of the reaction, a compound of formula (III), which is different from the one used during the first step of the reac15 tion, may be used.
Anhydrous tertiary amines, potassium hydroxide, sodium hydroxide, sodium bicarbonate, calcium carbonate, magnesium carbonate may be used as basic condensation agents.
In both a) and b) synthesis, anhydrides with organic or inorganic acids, asides, derivatives of phosphoric acids, alkylcarbonic acids may be used as compounds of formula (III).
Therefore, the reactive residue ¥ in compounds of formula (III) represents the residue of an inorganic or organic acid such as: chlorine, bromine, iodine» phosphite» azide, acyloxy or alkoxycartoony loxy.
The preferred group CO-Y-is the residue CO-CI.
The hydroxy functions in the Alkyl 3© formula (111) may be preferably protected by transformation into the corresponding acetales or ketals.
Examples of such protective groups may be for instance methvlidene, ethylidene, 1-methyl-ethylidene, 1-ethylethy lidene, 1-t-foutyl-ethylidene,. I-phenyl~ethylidene, 2,2,2-trichloro-ethylidene, 1-ethy1-propylidene., These groups may foe easily and fully submitted to hydrolysis through a short treatment with a strong acid, for instance diluted hydrochloric acid, ' aqueous trifluoroacetic acid or through a strongly acidic ion exchange resin, releasing the corresponding ketonic compounds, usually acetone, methylethylketone or diethyIketoneThe lower acyloxy protective C^-C^ groups, included in the R^ residue of formula (III), may foe -for instance acetoxy, propionyloxy, butyrovloxy and may toe IS easily submitted to hydrolysis by treatment with alkaline aqueous solutions, in order to. obtain the desired mono- or poly-hydroxyalkyl R groups of formula (I).
The reaction of a compound of general - formula (II·) with one of formula (III) to give a compound (IV) takes place preferably in an aprofeic solvent, such as, for instance, dime thy lacetamide (DMAC), dimethylformamide (DMF), hexamethylphosphoramide (ΗΜΡΪ) or dioxane, but also .in acetone, ethyl alcohol and isopropyl -alcohol. The temperature is not critical. The reaction takes place when temperature ranges from -10eC to + X50°C, preferably within 0°C and 100ec. 1.3- Diamxno-hydroxy- or hydroxyalkyl-propanes of general formula (II) are described in literature, for instance in 3ei1steins Handbuch der Organischen Che30 mie**: 1.3- diamino-2-hydroxy-propane, Beil.4 H 290, E II 739, E III 756, E IV 1694; 1.3- bis-(methylamino)-2-hydroxy-propane, Beil- 4 E IV 1695; 1.3- diamino-2,2-bis-hydroxymethyl-propanei> Beil. 4 E III 850; , 3-bis- (methylamino) -2,2-bis-hydroxymethyl-propane, Beil- 4 E III 851- When a compound of formula ill) is reacted with one of formula (III) in a molar ratio of 1:1 according. to synthesis b), then the 1,3-diaminoderivative of formula (II) is monoprotected on one of the two amino groups In order to avoid side-reactions- Protective groups which meet this purpose may be for instance acetyl, dichloroacetyl, trifluoroacetyl groups. Trx15 fluoro acetyl is particularly preferred. Afterwards, these groups may be easily and completely hydrolysed through treatment with alkaline aqueous solutions.
The reactive derivatives of the 3-(mono- or polyacy loxy) acyIamino-5-(mono- or poly-hydroxyalkyl) amino20 2,4,6-trixodo-benroic acids of general formula (III) are obtained by reaction of a reactive derivative of' a 3-(mono- · or poly-acyloxy)acylamino-2,4,6-triiodo-isophthalic acid of general formula (VIII) wherein St,, RiS, and Y are as previously defined, or by reaction of a derivative belonging to the' ones already described in patents OS 4,001,323 and EP 26281 with the hydroxy alky amines 2 -hydroxy-e thylamine, 1,3 -dihydroxy.isopropylamine (serinol), 2,3-dihydroxy-propylamine (isoserinol), 3-amino-l,2-,4-tautantriol, · or with the. corresponding N-mefchylamines, or with N-methylglucamine or with a corresponding derivative thereof wherein the hydroxy groups are preferably protected by chelatization, for instance with 5-amino-2,2-dimethy11., 3-dioxane, 5-amino-2-methy1-2-ethy1-1,3-dioxane, 510 amino-1,3-dioxane, 5-amino-2,2-diethy1-1,3-dioxane, 4aminomethyl-2,2-dimethyl-1,3-dioxolane, 4-aminomethyl2,2~diethyl-1,3-dioxolane, 5-amino-6-hydroxy-2,2-dimethyl-l,3-dioxeparte or 5-amino-6-hydroxy-2-ethyl-2me thy1-1,3-dioxepane15 The reactive derivatives of 3-(mono- or poly-acyloxy)acylamino-2,4,6-triiodo-isophthalic acid '(VIII) are generally reacted with one of the above mentioned amines in a molar ratio of about 1:2 without using a basic condensation agent, or in a x’atxo of 1:1 by using & basic condensation agent in an inert organic solventFor instance, dioxane or tetrahydrofuran (THE) are preferred solvents. The BY acid, released during the reaction of (VIII) with the amine, is neutralized ’by the second mole of the amine, giving the corresponding am25 moniura salt, or by-the basic condensation agent used.
Some of the preferred reactive derivatives of the 3-(mono- or poly-acyloxy)acylamino-5-(mono- or poly-hydroxyalkyl )aminocarbonyl-2,4,6-triiodo-benzoic acids of general formula (III) have already been described in 3© patents DE 2805928 or OS 4,139,605.
The compounds of this invention may be used as opacifying agents In non-ionic contrast media for X-ray diagnosIs» They may be formulated In a suitable carrier agent which is acceptable from the pharmacological point of view. Suitable carrier agents include, for instance, the ones which can be used for enteral or parenteral administration, such . as buffered sterile aqueous solutions containing tromethamine, phosphate, citrate and/or bicarbonate ions, ionically balanced solutions containing physiologically acceptable anions and cations such as: Cl^"\, nC03^~\ Ca/2+\, ' (2-1 and Mg « Solutions of the contrast agents of this invention may also contain a small amount of a physiologically tolerable chelating agent, such as the IS sodium and calcium salts of EDTA, in concentrations from 0,05 to 2 mM/1, or even heparin, at a dosage ranging from 5 to 500 units per 100 ml of solution, or another suitable anticoagulant agent.
Hypotonic solutions of the contrast media of this Invention may be isotonically balanced by adding the correct amount of Merlis liquid (The Am. J. of Phys. Vol- 131, 1940 p. 67-72) . Useful concentrations of Iodine for such contrast media vary from 140 to 500 mgl/ml at a dosage of '10-300 ml, according to the desl25 red diagnostic use.
The following experimental examples show the basic principles of this Invention.
EXAMPLE 1 1,3-bis- [ 3-( L-2-hydroxy-propionyl) amino-5- ί 1,3-dihydro~ 30 xy-isopropyl)-aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane. a) 124 g of 3-(L-2-acetoxy-propionyl)amino-5-(1,3dihvdroxy-isopropyl) aminocarbonyl-2,4, 6-triiodobenzoyl-chloride (0.162 .mol), obtained according to the procedure described in DB 2805928/Example 1, are solubilized in 490 ml of dime thy 1 for mamide (DMF). The resulting solution is cooled to 0-5°C, added of 32.4 g of anhydrous tributylamine (0.175 mol) and then, dropwise mixed under stirring with a solution of 7.66 g of l,3-diamino-2~hydroxy~ propane (0.085 mol) in 200 ml of DMF. The reaction mixture is kept under stirring at 0-5 eC for 1 h, then is left at room temperature for about 20 h.
Hence the . solvent is evaporated under vacuum»' The residue is crystallized with ethyl acetate. The crystalline precipitate is filtered and dried, then suspendend in 600. ml of water at 50eC- pH is adjusted at 10.3 with NaOH 2N and the mixture- is stirred until the acetoxy groups of the propionyl residues are totally hydrolysed. The resulting solution is mad® free from salts by passage R through ion exchange resins (360 ml of Amberlite IR 120 and 400 ml of DuoliteR A SOB). The eluate is evaporated to dryness and crystallized from 600 ml of ethyl alcohol. After filtration’ and drying 75.8 g of l,3-bis-[3-(L-2-hydro3cy-propxonyl)amino5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6triiodo-bensoyl-amino)-2-hydroxy-propane are obtained. yield: 64% m.p.: 280°C (dec.) Elemental Analysis (%) C BE I Calculated: 25.47 2.48 52.08 Found: 25.47 2.35 52.12lGM 436 -6.033 (c - 9.6% h2o) Solubility in H2O at 20 °C : > 100% w/v.
TLC: (Silica Gel 60 ^54 * Merck) N .76 .53 Eluent: CHC13/CH3OH/NH4OH 25% « 6/3/1 v/v/v. Rf = 0.14. HPLC: Rt s 12.4 min. Titre = 98,.5% (on the area) Chromatographic conditions: Column: LICHROSORB^P 18 (Merck), 5 μ (250 x 4 mm) Eluent: A) H2O B) CH-jCN Gradient (flow 1 ml/min: Detector 07 254 nm): time (min) = 0-3: 3-25; 25-30 %B -·= 0; 0 — 40; 40 b) the above disclosed compound can be obtained also by reacting, according to the procedure of the previous Example la), 65.2 g of 3-(L-2-acetoxypropxonyl)amino-5-(4,4-dimethy1-3,5-dioxa-cyclohexyl)aminocarbony1-2,4,6-triiodo-benzoylchlorxde (0.081 mol), described in DE 2805928/Example lB(b), with 3.83 g of 1,3-diamino-2-hydroxypropane (0.042 mol) in 350 ml of DMF in the presence of 16.2 g of tributylamine (0.087 mol). The obtained product is transformed into 1,3-bis(3- (ϊ,-2-acetoxy-propionyl) amino-5- (1,3-dihydroxyisopropyl ) aminocarbony1-2,4,6-triiodo-benzoyI-amino]-2-hydroxy-propane by treatment with HCl 2N and corresponding elimination of acetone. This product is suspended in water -at 50"C, the pH is-adjusted to 10.3 with NaOH 2N and the basic treatment continues Until the aeetoxy groups are completely hydrolysed» After elimination of the ionic species, due to the. passage through ion exchange resins, 41.4 g of X,3-bis-(3-(1-2-hydroxypropionyl) amino-5- (1,3-dihydroxy-isopropyl) aminocarbonyl-2 p 4,6-triiodo-benzoyl-amino]-2-hydroxypropane are obtained with a yield of 70%» c) This reaction may also be performed in ethyl alcohol (EtOH) instead of DMFs 588 g of 3-(1-2acetoxy-propionyl 5 -amino-5- (1,3-dihydroxy-isopropyl) aminocarbonyl-2,4,6-triiodo-benzoy1-chloride (0,57 mol) in 5.8 1 of EtOH are reacted at room temperature with 36.4 g of 1,3-diamino-2-hydroxypropane (0.404 mol) dissolved in 2.9 1 of EtOH, in the presence of 144 g of tributylamine (0.777 mol). The obtained precipitate is filtered, suspended in water and treated with· NaOH 2N up to pH 10.3 as previously described xn a). 350 g of 1,3-bis- (3-( L-2-hydroxy-prop! onyl) -amino-5- (1,3dxhy droxy-isopropyl) aminocarbonyl-2,4, β-tr iiodobenzoyl-amino)-2~hydroxy-propane are obtained with a yield of 62.2%.
EXAMPLE 2 1,3-bis- [ 3-hydroxyacetylamino-5- (1,3-dihy droxy-isopropyl ) aminocarbonyl-2,4,6-triiodo-benzoyl-amino3-2,2-bishydroxymethy1-propane. a) 144 g of 3-acetoxyacetylamino-5-(1,3-dihy droxyisopropyl) aminocarbonyl-2,4,6-triiodo-benzoylchloride (0.192 mol), described in DE 2805928/Sxaarole 10, dissolved' in 600 ml'of TOMS', are dropwise added under stirring and between 5 to 10 *C to a solution of 13.4 g of X,3-diamxno-2„218 bis-hydroxymethyl-propane (0.10 mol) and 39 g of tributylamine (0.21 mol) in 30 ml of DMF. The reaction mixture is kept under stirring for some hours at 10-20 :’C. Hence It'is poured under heavy stirring into 5.5 1 of ethyl acetate from which the final product crystallizes. After filtration and- drying, 140 g of raw l,3-bxs-[3-acetoxyacetyl~ araino-5- (1,3-dihydroxy-isopropyl) aminocarbonyl2,4, 6-tr iiodo-benzoy 1-amino ]_2,2-bxshydroxymethyl-propane are obtained.
A sample crystallized from methyl alcohol has the following characteristics: m.p.: 284-287*0 Elemental Analysis (%) C Calculated: 26.91 Found: 26.82 H 1 N 2.58 48.74 5.37 2.70 48.45 .5.37 b) 105 g of raw l,3-bis-[3-acetoxyacetylamino-5-(l,3dihydroxy-isopropyl) aminocarbonyl-2,4,6-tr iiodobenzoy X-amino 3-2 ,2-bis-hydroxymethyl-propane are diluted- in 1.9 1 of water and 0.8 1 of methyl alcohol (CHgOH) and slowly mixed with 170 ml of NaOH IN until a constant pH value of 10.3 Is obtained- The mixture Is kept under stirring for about 10 h at 20^0. Then, the 'methyl alcohol Is evaporated under vacuum- The resulting aqueous solution is made free from salts by passage through ion exchange resins (160 ml of Amberlite IR 120 and 150 ml of Duolite^ A SOB)» The eluate Is evaporated to dryness under vacuum, diluted again in 1.2 1 of water, bleached on active carbon and percolated on 1200 ml of AmberliteR XAD-2. The fractionscontaining the product are gathered and dried- 66 g of l,3-bis-(3-hydroxyacetylamino-5(X,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-trxiodo-henzoyl-amino]~2,2-bis-hydroxymethyl-propane are obtainedThe last impurities are eliminated by. dissolving the product in aqueous ethyl alcohol 80% and filtering the turbid solution.
Yield: 62% Elemental Analysis (%) C Calculated: .25.19 Found: 25.26 TLCs (Sili< m-p. : 285aC H I N 2.45 51.51 5.68 2.60 51.36 5.57 Gel 60 F254, Merck) [ 25% = 3/2/1 v/v/v. Rf = 0.23. Titre - 99% (on the area.) HPLC: Rt - 9.6 min.
Chromatographic conditions: Column: as reported in Example 1 Eluent: A) KH2PO4 0.01 M 3) H2O 75%, CH3CN '25% Gradient (flow 1 ml/iain; Defector 07 254 nm): time (min) = 0-5; 5-15; 15-25 %B = 20; 20 - 80? 80 In the same way the following compounds are 'obtained: .- 1, '3-fois- [3-hydroxyacetylamino-S- (2,3-dihydroxypropyl) aminocar bony 1-2,4,6-tr iiodo-benzoy X-amiao ]| 2.2- bis-hydroxymethyl-propane- . : 1.3- bis- [3-hydroxyacetylamino-5- ¢1,3,4-trihydroxy2-butyl) aminocarbonyl-2,4,6-trxiodo—benzoy lamino 1 2,2-bis-hydroxymefchy1-propaae.
EXAMPLE 3 1,3-bis- [ 3- (L-2-hydroxy-propiony 1) amino-5- (2,3-dihydroxy-propyl )arainocarbony 1-2 ,4, 6-triiodo-benzoylamino]-2-hydroxy-propane. 197 g of 3-(L-2-acetoxy-propiony 1)amino-5-(2 ,,3dihydroxy-propyl) aminocarbonyl-2,4,6-triiodo-benzoyl~ chloride (0.25 mol), described in DE 2805928/Example 6, are reacted in 500 ml of DMF and in the presence of 55-6 g of tributylamine (0-30 mol) with 11.3 g of 1,ΒΙΟ diamino-2-hydroxy-propane (0.125 mol) according to the procedure described in the Example 2a). The condensation product is submitted to hydrolysis, as described in the Example 2b). Similarly, the isolation and the purification of the final product are performed. 94.2 g of 1,3-bis-[3-( L-2-hydroxy-propionyl)amino-5(2,3-dihydroxy-propyl) aminocarbonyl-2,4,6-tri iodo-ben- zoyl-amino]-2-hydroxy-propane are obtained. Yield: 50% m.p.: 278-282°C Elemental Analysis (%) C H 1 N Calculated: 25.47 2.48 52.09 5.75 Found: 25.21 2.53 51.89 5.59 TIsC: (Silica Gel 60 E,34, Merck) Eluent: CHC13/CH3OH/NH4OE 25% = 6/3/1 v/v/v. Rf = 0.24.
HBliG: Rt .= 15.4 min. Titre = 99.4% (oh the area) Chromatographic conditions: Column: LXCHROSPEER^RPlg (Merck), 5 μ (250 x < mm) Eluent: A) 0.1 M 3) H20 50%, CSgCN 50 % Gradient (flow 1 ml/min; Detector W 254 nn): time (min) = 0-5; -5-20; 20 - 30; 30 - 35 %B = 10; X0 - 28; 28 - 70; EX&HPU5 4 1,3-bis-13 — C L-2-hydroxy-propionyl) amino-5- (1,3,4-tr ihydroxy-2-touty 1) aminocarbonyl-2,4. f 6-tri iodo-benzoylamino3-2-hydroxy-propane24 g of 3-(L~2-acetoxy-propionyl)araino-5-(l»3,4trihydroxy-2-butyl)aminocarbony1-2,4,6-triiodo-benzoylchloride (0.03 mol), obtained by known methods described in DI 2805928, in 30 ml of DMF and In presence of 3.8 g of triethylamine (0.037 mol) are reacted with a solution of 1.45 g of 1,3-diamino-2-hydroxy -propane (0.016 mol) in 30 ml of DMF at 5 to 8eC, according to tne procedure descrroed xn Example 3. 7.2 g of the title comoound are obtained.
Yield: 30% Elemental Analysis (%) c Calculated: 26.05 Found: 26.04 M 436 = "5.01e' Solubility in H90 at 20*®C TLC: (Silica Gel 60 Eluent: CHClg/(HjOH/NHjQE H-and JC-NMR spectra proposed structure.
EXAMPLE S m.p.: 250-256°C B X N 2.65 50.02 5.52 2.95 49.15 5.33 (c = 10.13% h2°) 100% w/v 25% = 5/4/1 v/v/v. Hf = 0.24. are In accordance with the 1,3-bis- [ 3- (L-2-hydroxy-propionyI) amino-5- (N-methyl-N• (D-l-deoxy-glucitol)3 aminocarbonyl-2,4,6-triIodo-bensoy1-smino]-2-hydroxy-propane. .6 g of 3-CL-2-acet©xy-propIonyl)amIno-5~|iN-methyl-N-(D-l-deoxy-glucitol)) aminocarbonyl-2,4,6- triiodo-benzoyl-chloride (0.024 mol), obtained toy known methods described in DE 2805928, in X00 ml of DMP are reacted with a solution of 1-124 g of l,3-diamino-2~hydroxy-propane (0-012 mol) and 2-53 g of triethylamine (0.025 mol) in 30 ml of according to the procedure described in Example 3. 9.26 g of the title compound are obtained.
Yield: 47% m.p.: 266eC (dec.) Elemental Analysis (%) C H I N Calculated: 28.04 3.14 45.58 5.03 Pound: 28.19 3.29 45.48 5.03 ex)20„e = -is· (c = 7.04% h2o) 13 C-NMR spectrum is in accordance with the proposed structure.
In the same way the following compounds are obtained: ~ l,3-bxs-i3-(L~2-hydro3qf-propionyl)araino-5-iN-methyl-N- (1., 3-dihydroxy-isopropyl) 3 aminocarbonyl2,4,6-triiodo-benzoyl-amino)-2-hydroxy-propane. - 1,3-bis-(3-(L-2-hydroxy-propionyl)amino-5-(N-me20 thy3.-N—(2,3-dihydroxy-propyl) ]amxnocarbonyl-2,4,6triiodo-benzoy1-amino]-2-hydroxy-propane. e 1,3-bis-[N-methyI-S-(3-(L-2-hydroxy-propionyl)amino-5(2-hydroxy-ethyl)aminocarbonyl-2,4,β-triiodo-benzoyl325 amino 3-2-hydroxy-propane 20.85 g of 3-(L-2-acetoxy-propionyl)amino-5-(2-hydroxy-ethyl) aminocarbonyl-2 4, β-t riiodo-benzoy1-chloride (0.025 mol), obtained by known methods described in DE 2805928, in 80 ml of DMF are reacted with a - -solution of 1.47 g o£ l,3-bis-(methylamxno)-2-hydroxy-propan® (0.012 mol) and 2.63 g of triethylamine (0.026 mol) in ml ox DMF at 5°C to room temperature, according to the procedure described in Example 3. 9.6 g of the title compound are obtained.
Yield: 56% Elemental Analysis (%) C m.p.s 285eC (dec.) B 2.54 2.,43 53-24 52.81 N .88 .78 (c ® 9.95% H-,0) Calculated: 26.03 Found: 25.86 P<)2°43S - -3.85° 13 B-and C-NMR spectra are in accordance with the proposed structure.
EXAMPLE 7 I, 3-bxs- (N-methy 1-N- (3-(L-2-hydroxy-propionyl) amino-5(1,3-dihydroxy~isopropyX)aminocarbonyl-2,4,6-trixodobenzoyl)amino)-2-hydroxy-propane. 21.4 g of 3-(I»-2-acetoxy~propionyl)amino-5-(ly3~ dihydroxy-isopropyl)aminocarbonyl-2,4,6-trxiodo-benzoylcbloride (0.025 mol), obtained by known methods described in DE 2805928, in 85 ml of DMP are reacted with a solution of 1.47 g of l,3-bis-(methylamino)-2hydrossy-propane (0.012 mol) and 2.63 g ox triethylamine (0.026 mol) in 30 ml of DMF at 5®C to room temperature, according to the procedure described in Example 3.
II. 1 g of the title compound are obtained.
Yield: 62% Elemental. Analysis (%) C Calculated: 26.60 26.31 -3.54* m.p»: 295°C (dec.) H 2.70 2.95 I 51.09 50.68 N .64 .48 Found: ,20 ίεΠ’ Solubility in HjO at 22^0: > 100% w/v .44% B20) 436 Ί 1 *3 H-and C-NMR spectra' are in accordance with the proposed structure.
EXAMPLE 8 1,3-bis- [ N-methy l-N- [ 3- (1—2 -hydroxy-propionyl) amino-5(2.,3-dihydroxy -propyl) aminocarbonyl-2,4,6-triiodobenzoyl 3 amino]-2-hydroxy-propane.
Title compound is obtained by reacting the desired reagents in the same quantities disclosed in Example 7 and following the same procedure. 7.9 g of final compound are obtained. Yield: 44% Elemental Analysis (%) m.p.: 28Q*C (dec.) C H I N Calc.: 26.60 2.70 51.09 5.64 Pound: 26.32 2.81 50.24 5.44 436 = -3. 2° (c = 9.8% H2O) Solubility in at 203C >100% w/v 13 x* C-NMR spectrum is in accordance with (H9O=1.54%) the proposed structure. example 9 1,3-bis- ( N-methy 1-N- (3-( L-2-hydr oxy-propionyl) amino-5(1,3,4-trihydroxy~2-butyl) aminocarbony1-2,4,6-triiodobenzoyl3 amino]-2-hydroxy-propane. 19.9 g of 3-(L-2-acetoxy-propionyl)amino-5-(l,3,4trihydroxy-2-butyl) aminocar bony 1-2,4,6-tr iiodo-benzoy 1ehloride (0.025 mol), obtained by known 'methods described in DE 2805928, in 30 ml of DHE are mixed with 3.8 g of triethylamine (0.037 mol), 'then are reacted with a solution of 1.5 g of 1,3-bis-(methylamino)-2rhydroxypropane (0.013 mol) in 25 ml of DMF at 5® C to room temperature, according to the procedure described in Example 3. .68 g of the title compound are obtained.
Yield: 29.5% m.p.: 256,3C Elemental Analysis (%) C Ξ I N Calculated: 27.12 2.86 49.12 5.42 Found: 27.46 3.15 48.55 5.24 t«)2%36 " -3-16" (c = 9.93% H90) 1 1 *3 H-and x C-NMR spectra are in accordance with the proposed structure.
EXAMPLE 10 1-(3-( L-2-hydroxy-propionyl) amino-5- (1,3-dihydroxyisopropyl) aminocarbony 1-2,4,6-triiodo-benzoyl-amino]-3- (3hydroxyacetylamino-5- (2,3-dihydroxy-propyl) aminocarbony 1-2,4,6-triiodo-benzoyl-amino3-2-hydroxy-propanea) 125 g of 3-(L—2-ac©toxy-propionyl)amino-5-(l,3-dihydroxy-isopropyl) aminocarbony 1-2,4,6-tr ixodobensoyl-chloride (0.163 mol), diluted in 150 ml of DMF, are dropwise added, while keeping the temperature between 0 and 10 ®C, to a solution of 45.6 g of l-trifluoroacetylamxno-2-hydroxy-3-aminopropane trifluoroacetate (0.152 mol) and. 35..8 g of triethylamine ¢0-35 mol) in 280 ml of DMF. The resulting mixture is stirred at 10aC for 8 hAffcer filtration, the solution is evaporated to dryness, then is diluted with 3 1 of methylene chloride (CH2cl9). The condensation product precipitates, then, after filtration, the protective groups are removed toy hydrolysis, according to the procedure described in Example 2b). The resulting product is purified by means of fixation on a 120) and subsequent elution with about 6 1 of SH^OH 2M. After evaporation of the solvent, 76-S g of 1-(3-( L-2 -hydroxy -propionyl) amino-5- (1 „ 3-dihydroxyisopropyl) aminocarbonyl-2,4,6-triiodo-benzoylamino)-2-hydroxy-3-amxno-propane are obtained with a yield of 65%.
Acidimetric titre « 99.4% m.p.: 211,a,C b) 73.5 g of 3-acetoxyacetylamino-5-(2,3-dihydroxypropyl) aminocarbonyl-2,4,6-trxiodo-benzoyl-chloride (0.098 mol) in 500 ml of DMF are slowly added drqpwise, at a temperature between 5 and 10 °C, to a solution of 76 g of the produet obtained at point a) (0.098 mol) and 11.1 g of trxethylamine (0.11 mol) in 500 ml of DMF- The mixture is kept under stirring for 20 h, then filtered and dried. The residue is dissolved in 1.9 1 of water and 0.8 1 of methyl alcohol, then it is submitted to hydrolysis and purification according to the procedure described in Example 2b)» 92 g of 1-(3(L-2-hydroxy -propionyl) amino-5- (1,3-dihydroxy-isopropyl) aminocar bony 1-2,4,6-tr iiodo-benzoy i-amino]3- (3-hydroxyacetylamino-5- (2 ? 3-dihydroxypropyl) aminocarbonyl-2,4,6-tr iiodo-benzoy l-aminoj-2-hydroxypropane are obtained.
Yield: 64.8% m.p-: 300eC Elemental Analysis (%) Calculated: 24.88 2.37 52.58 -80 24.70 2-29 52.15 -74 Found: -2.9° (c - 10% H^O) TLC: (Silica Gel 60 Eluent: CHC^/CHgOH/NH^OH 25% = 6/3/1 v/v/v. Rf = 0.18. HPLC: Rt.= 13.6 min. Titre = 97.5% (on the area) Chromatographic conditions: Column: as reported In Example 1 Eluents: A) K2PO4 0.01 Μ B) KH2PO4 °"θ1Μ 50%* CH^CM 50% Gradient (flow 1 ml/min; Detector DV 254 nm): time (min)· « 0-6; 6 - 25; 25 - 30 %B « 2; 2 -80; 80 EXAMPLE 11 1-[3-hydroxyacetylamino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo~benzoyl-amino3-3-i3-(L-2hydroxy-propionyl) amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2 14,6-triiodo-banzoyl-araino] -2-hydroxypropane.
Title compound is obtained following the procedure described in Example 10.
So 8.58 g of 3-acetoxyacetylamino-5-(l,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoy1-chloride (0..011 mol) in 60 ml of DMF are reacted with a solution of 8.54 g l-[3-(L-2~hydroxy-propionyX)amIno-S(13-dihydroxy-isopropyl) aminocarbonyl-2,4,6-triiodobenzoyl~amino]-2-hydroxy-3-amino-propane (0.011 mol), obtained according to Example 1© a), and 2.22 g of triethy lamine (0.022 mol) In 60 ml of DMF to give the desired, compound. 8.75. g of the title compound are obtained.
Yield: 51% m.p.: 283e'C (dec.) Elemental Analysis (%) C E 1 N Calc.: 25.19 2.45 51.51 5.68 Found: 24.13 2.72 48.88 5.32 (Η,Ο « 2.71%) [0436 " 2.6° (C = 10.44% Β^Ο) Solubility in Β^Ο at 25®C: >100% w/v Τ3 " C-NMR spectrum is in accordance wxth -the proposed structure.
EXAMPLE 12 1-(3-( L-2-hydroxy-propionyl) amino-5- (1,3 -dihy dr oxy isopropyl ) aminoearbonyl-2,, 4., 6-triiodo-bensoyl-cimino 3-3-( 3(L-2-hydroxy-propionyl) amino-5- (2,3-dihydroxypropyl) aminoearbonyl-2 .,4,,, 6-triiodo~ben2oyl-amino]-2-hydroxypropane .
Following the procedure described in Example 10,, 8.75 g of 3-(L-2-acetoxy-propionyl)amino-5-(2,3-dihydroxy-propyl) aminocarbonyl-2,4,6-tr iiodo-benzoyl-chloride (0.01 mol) in 60 ml of DMF reacted with' a solution of -7.76 g l-(3-iL-2-hydroxy-propionyl)aminc—5(1,, 3-dihydroxy-isopropyl) aminocarbonyl-2,4 » 6-trliodobenzoyl-amino ] -2-hydroxy-3-amino-propane' (0.01 mol)., obtained according to Example 10 a), -and 2.02 g of triethylamine (0.0 2 desired compound. 8. tained.
Yield: 55% Elemental Analysis (® C Calculated: 25.46 Found: 25.49 ^2°436 " ~5’ S7* Solubility In S^0 at 13C-NMR spectrum Is mo3 in 60 ml' of DMF to give the 15 g of the title compound are ob- n m. ,p.s 287ec Cdec.) oi Ξ 1 ’ N 2.48 52.08 5.75 2.34 51.67 5.73 (c S3 10.01% b20) 20 5 >100% w/v in accordance with the proposed structure.
EZ&HPLE 13 1-(3-( I»-2—hydroxy—propionyl ) amino-5- (1,3-dihydroxyisopropyl) aminocarbonyl-2,41,6-trixodo-benzoyl-amino J-3-(3(L-2-hydroxy-propionyl) amino-5-(N-methyl-N-(D-l-deoxyglucitol) )aminocarbonyl-2,4 f 6-triiodo-benzoyl-amino)-2hydroxy-propane.
Following the procedure described in Example 10, 6..9 g of 3-(L-2-acetoxy-propionyl)-5-(N-methyl-N-(D-ldeoxy-glucitol) ] aminocarbonyl-2 ,.4,6-triiodo-benzoylchloride (0.008 mol) . in 50 ml of DMF are reacted with a solution of 6.13 g 1-((L-2-hydroxy-propionyl)-5-(1,3dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl- amino 3 -2-hydr oxy-3 -amino-propane (0.008 mol), obtained according to Example 10 a), and 1.6 g of triethylamine (0.016 mol) in 50 ml of DMF to give the desired compound. 4.2 g of the title compound are obtained.
Yield: 34% Elemental Analysis (%) C Calculated: 26.84 Found: 27.29 l«l2043s = -11.9° m.p.: 285®C (dec.) Solubility in at 20°J C-NMR spectrum is in structure.
E I N 2.83 48.62 5.37 2.92 ’ 48.62 5.22 « 5.0% H2O) >100% w/v accordance with the proposed ΕΪΚΒΒΙΒ 14 1,3-bis- (3-hydr oxyacetylamIno-5- C1,3-dihy droxy-isopropyl ) aminocarbonyl-2, 4,6-triiodo-bensoyl-amino ] -2.hydroxy-propane. 112.5 g of 3-acefcoxyacetylamino-5-(l,3-dihydroxy~ isopropyl) aminocarbonyl-2,, 4,6-triiodo-benzoyl-chloride (0..15 mol), described in DE 2805928/Example 10, in 400 sal of DMF are reacted with 16-7 g of trxethylamine (0.165 mol) and with 7.13 g of 1.,3-diamino-2-hydroxypropane (0.075 mol), according to the procedure described In Example 2. g of X,3-bis-[3-hydroxyacetylamino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-trIIodo-benzoylaminoJ-2-hydroxy-propane are obtained.
Yield: 56% m.p.: > 280"C Elemental Analysis (%) C H I N Calculated: 24.49 2.25 53.10 5.86 Found: 24.19 . 2.28 53.26 5.83 TJX: (Silica Gel 60 F25V Merck) Eluent: CHClg /CH'3OE/NH4 OH 25% = 3/2/1 v/v- Rf = 0.60. HPLC: Rt = 7.1 min. Titre - 99% (on the area) Chromatographic conditions: as reported In Example 2.
B2A>S?X,,S IS lr3-bis-[3-hydroxyacetylamino-5"(l,3,4-trihydroxy-2~butyl) aminocarbonyl-2,4,6-triiodo-benzoyl-amino ] -2-hyd.roxy-propane. 23.4 g of 3-acetoxyacetylamino-5-(l,3,4-trxhydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chloride (0.03 mol), obtained toy known methods described in DE 2805928, in 25 ml of DMF 'are reacted with 3.8 g of trxethylamine (0.037 mol) and with 1.45 g of.l,3-diamino-2-hydroxy-propane (0.016 mol), according to the procedure described In Example 2. 4.7 g Of the title compound are obtained.
Yield: 21% m.p.: 275-C Elemental Analysis (%) C Calculated: 24-92 Found: 24-93 H 2-43 2.50 I 50-96 49.98 N .62 -53 Solubility in at 20®C: 100% w/v In the same way the following compounds axe obtained: - 1,3-bis-(3-hydroxyacetylamino-5-'( 2,3-dihydroxypropyl) aminocarbonyl-2 ,, 4 r 6-trixodo~benzoyl-amino ] -2hydroxy-propane„ - 1,3-bis-(3-hydroxyacetylamino-5-[N-methyl-N-(1,3dihydroxy-isopropyl) J aminocarbonyl-2,, 416-triiodobenzoyl-amino 'j -2-hydroxy -propane. - 1,3-bis~[3-hydroxyacetylamino-5-(N-methy1-N-(2,3dihydroxy-propyl)3 aminocarbonyl-2,4,6-txiiodo-benzoy l-amino3-2-hydroxy-propaneE3CAMPIS IS 1,, 3-bis - [N-methy 1-N- (3-hydroxyacety lamino-5- (1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl]amino]-2-hydroxy-propane23.4 g of 3-acetoxyacetylamino~5-(l,3,4-trihydro~ xy-2-butyl)aminocarbonyl-2,4,6-triiodo-benzoyl-chlorxde (0-03 mol), in 25 ml ox DMF are reacted with 3.8 g of triethylamine (0-037 mol) and with 1-9 g of 1,3-bis(methylamxno3-2-hydroxy-propane (0-016 mol), according to the procedure described in Example 2.7 g of the title compound are obtained.
Yield: 30% Elemental Analysis (%) C Calculated: 26.04 Found: 26-12 m-p.: 2S3eC Ξ I N 2.65 50-02 5-52 2.69 50.86 S.57 Solubility in H20 at 20"C: 100% w/v EXAMPLE X7 1,3-bis- (N-methy 1-N~ (3-hydroxyacetylamino-5- (N-methylN-(D-l-deoxy-gluc itol)]aminocarbony1-2,4,6-triiodobenzoyl 3 amino ] -2-hydroxy-pr qpane» g of 3-ace toacv ace tylamino-5-[ N-methyl-N-(D-ldeoxy-glucitol)3 aminocarbony1-2,4,6~triiodo~benzoyl~ chloride (0-028 mol), obtained by known methods described in DE 2805928, in 100 ml of DMF are reacted with a solution of Γ. 65 g of 1,3-bis-(methylamino)~2-hydro3[yprooane (0.014 mol) and'2.93 g of triethylamine (0.029 mol) in 30 ml of DMF, according to the procedure described in Example 2. .14 g of the title compound are obtained.
Yield: 41% Elemental Analysis (%) m.p.: 276®C (dec.) Calculated: C 28.04 27.95 H 3.14 3.21 I 45.58 45.48 N .03 4.97 Found: rcCi — 436 Solubility in H90 at 25eC: >100% w/v ~ C-NMR spectrum is in accordance with the proposed structure.
In the same way the following compounds are obtained: - 1,3-bis-(N-methyl-N-E 3-hydroxy acetylamino-5-( 1,3dihydroxy-isopropy1)aminocarbony1-2, 4,6-triiodobenzoyl3 amino 3-2-hydroxypropane. 1t3-bis-[N-methyl-N-[ 3-hydroacy ace tylamino-5-(2,3dihydroxy-propyl) aminocarbonyl-2,4,6-triiodo~benzoy13amino3-2-hydroxy-propane-12.63 (c = 10.6% S2O) EXAMPLE X8 e 3-bis- (N-raethy1-N- (3-hydroxyacetylamino-5-(N-methylN-(1,3-dihydroxy-isopropyl) ]aminocarbonyl-2,4,6-triiodo-benzoyl3amino3-2-hydroxy-propane. 21.31 g of 3-acetoxyacetylamino~5~[N~methyl-N(1,3-dihydroxy-isopropyl) ]aminocarbonyl-2 s 4,6-triiodobenzoyl-chloride (0-025 mol), obtained by known methods described in DE 2805928, in 95 ml of DMF are reacted with a solution of 1.47 g of 1,3-bis-(methylamina)-2hydroxy-propane (0.12 mol) and 2.63 g of trie thy lamine (0.026 mol) in 30 ml of DMF, according to the procedure described in Example 2» 8.1 g of the title compound are obtained.
Yield: 45% m.p.: 290eC Elemental Analysis (%) Calc-: Found: C 26.98 26.29 H 2.86 3.01 50.33 50.21 100% w/v N .55 S-24 (¾0 1-02¾) Solubility in H20 at 25°C: spectrum is in accordance with the proposed structure.
EXAMPLE 19 1,3-bis- (3- (N-methyl-N-hydroxyacetyl) amino-5- (1,3-dihy'droxy-isopropyl ).aminocarbonyl-2,4,6-triiodo-benzoylamino]-2-hydroxy-propanea) 46 g of 3-(N-methyl-N-acetoxyacetyl)amino-2,4,6triiodo-isophthaloyl-dichloride (0.065 mol), .described in EP 26281/Example 11, in 250 ml of anhydrous tetrahydrofuran (THE) are added, dropwise to 12.6 g of 1,3-dihydroxy-isopropylamine '(0.138 mol) in 100 ml of THE- The mixture is kept for 3 h at room temperature under stirring. Then it is filtered and evaporated to dryness under vacuum. The residue is constituted by 50.4 g of 3-(N~ raethyl-N-acetoxvacetyl) amino-5- (1,3-dihy dr oxy-isopropyl ) aminoearbony1-2,4,6-trxiodo-benzoyl-chloride. b) 50 g of 3-(N-methyl-M-acetoxyacetyl)amino-5-(l,3dihydroxy-isopropyl) aminocarbonyl-2,4,6-triiodobenzoy l-chlorids (about 0.065 mol), obtained according to a), diluted In 200 ml of DMF, are reacted with 3 g of l,3-diamino-2-hydroxy-propane (0.034 mol) in 100 ml of DMF, according to the procedure described in Example 1. g of l,3-bis-i3-(N~methyl-N-hydroxyacefcyl)amino-5- (1»3-dihy dr oxy-isopropyl) aminocarbonyl-2,4 ,«6-triiodo-benzoy 1-amino)-2-hydroxy-propane are obtained.
Yield: 44.2% m.p.: > 250°C Elemental Analysis (%) C H I N Calculated: 25.47 2.48 52.08 5.75 Found: 25.82 2.60 52.37 5.62 TLC: (Silica Gel 60 F954, Merck) Eluent: CHC13/CE3OH/NH4OH .25% « 6/3/1 v/v/v. Rf 0.23 HPLC: Rt = 14.6 min- Titre = 96. 7% (on the area) Chromatographic conditions: as reported in Example 2. c) This product may be also obtained by N-methylation of the compound already described in Example 14. 14.3 g of l,3-bis-i3-hydroxyacetylamino-5-(l,3-dihydr oxy-isopropyl) aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propane (0.01 mol) in 500 ml of anhydrous DMF are mixed under stirring with a solution of 1-08 g of sodium methylate (0-02 mol) in 30 ml of methyl alcohol. After 3 h, methyl alcohol is removed by distillation. An excess of methyl iodide is added and the solution is stirred for one day at room temperature- Then the reaction mixture is poured under stirring in 600 ml of ethyl acetate and the raw product precipitatesThis one is filtered, diluted in water and made free from salts by passage through ion exchange resins (Amberlite1* IR 120 and IRA 400)- The eluate is treated with active carbon and evaporated to dryness 7 g of l,3-bis-[3-(N-methyl-N-hydroxyacetyl)amino5-(1,3-dihydroxy-isopropyl)aminocarbonyl-2 , 4,6-triiodobenzoyl-amino 1-2-hydroxy-propane are obtained · with a yield of 47-9%. This compound is identical to the one obtained through process b)» In the same way the following compound is obtained: l,3-bis-[3-(N-methyl-K-(L-2-hydroxy-propionyl) ]amino-5-(1,3,4-trihydroxy-2-hutyl)aminocarbonyl2,4,6-triiodo-benzoyl-amino]-2-hydroxy-propaneEXAMPLE 2S 1,3-bxs-(3-ίH-methyl-N-(L-2-hydroxy~propionyl))amino-5{1,3-dxhydroxy-iscpropyl) aminocarbonyl-2,4, β-triiodobenzoy l-amino 3-2-hydroxy-propane. 80.4 g of l,3-bis-i3-(L-2-hydroxy-propionyl)amino5-(1,3-dihy dr oxy-isopropy 1) aminocarbonyl-2,4,6-tr iiodobenzoy l-amino 3-2-hydroxy-propane (0.055 mol), described in Example 1, are dissolved in 900 ml of DMP and: mixed under stirring with 132 ml of sodium methylate 1 M in methyl alcohol (0,132 mol). Methyl alcohol Is removed by distillation- Hence, 23.7 g of diraethylsulphate (0-188 mol) are dropwise added at a temperature of 5C.
Stirring is maintained for about 1 h, then the solvent is removed by vacuum distillation. The raw material is diluted with ethyl acetate and forms a solid powder, which Is filtered, diluted in water and made' free from R salts by percolation on ion exchange resins (Amberlit a IR 120 and Duolite^ A 30B). The solution is evaporated to dryness and then dissolved in boiling ethyl alcoholAfter some days, 62. g of 1,3-bis-(3-(N-methyl-N-(L-2hydroxy-propionyl))amino-5- (1,3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]~2~hydroxy~ . propane crystallizeYield: 75.6% m.p.: > 300°C (dec.) Elemental Analysis (%) C Calculated: 26.60 Found: 26-58 C'^2°436 +29"7° In 250 ml of DMF, 102 g of the product described in Example 3 (0.07 mol) are reacted with 150 ml of sodium methylate 1M in methyl alcohol (0.15 mol), and with 30 g of metansulphonate methyl· ester (0.27 mol), according to the procedure described in Example 20. 42.6 g of l,3-bis-[3-iN-methyl-N~(L-2~nydroxy~pro pionyl)3amino-5-(2,3-dihydroxy-propyl)aminocarbonyl2,4 » 6-fcriiodo-benzoyl-amino3-2-hydroxy-propane are ob tained.
Yield: 41% Elemental Analysis (%) C Calculated: 26.50 Found: 26.24 EXAMPLE 22 m.p. : 284*C s I N 2.70 51.10 5.64 2.80 50.88 5.47 1,3-bis- (3-( N-methy1-N-hydroxy acetyl) amino-5~ (2,3-dihydroxy-propyl)aminocarbonyl-2,4,β-triiodo-benzoyl-amino 3-2-hydroxy-propane. g of 3-(N-methy 1-N-acetoxyacefcyl} amino-2,4,6triiodo-isophthaloyl-dichloride (0.032 mol), described in EP 26281/Sxample 11, are reacted with 5.8 g. of 2,3dihydroxy-propylamine (0.064 mol) in THF according to the procedure described in Example 19a). The resulting product is 3-(N-methyl-N-acetoxyacetyl)amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6-triiodo-benzoylchloride, which is reacted in DMF with 1.5 g of 1,3diamino-2-hydroxy-propane (0.016 mol). The resulting product is isolated and. purified according to the procedure of Example 1. 11 g of 1,3-bis-[3-(N-mefchyl-N-hydroxy acetyl) amino-5- (2,3-dihydroxy -propyl) aminocarbonyl-2 ,4,6-trxiodo-benzoyl-amino3-2-hydroxy-propane are obtained.
Yield: 47% m.p.s 295°C (dec.) Elemental Analysis (%) C Η I N Calculated:. 25.47 ’ 2.48 52.08 5.75 Found: 25.97 2-50 51.71 5.77 In the same way the following compound is obtained: - 1,3-bis-[ 3-(N-methyl-N-hydroxy acetyl) amino-5(1,3,4-trihydroxy~2-butyl) 3aminocarbonyl-2,4,6triiodo-benzoyl-amino]-2-hydroxy-propane.
E3»E 23 1,3-fois-(3- (L-2-hydroxy-propionyl) amino-5~ (1,, 3-dihydroxyisopropyl)aminocarbonyl-2e4„6-triiodo-benzoyl-amino]2,2-bis-hydroxymethyl-propane.
Following the procedure described in Example 2, the 3-( Is-2-acet oxy-propionyl) amino-5- (1,3-dihydroxyisopropyl) aminocarbonyl-2 , 4,6-triiodo-benzoyl-chloride is reacted in DMF with It, 3-diamino-2,2-tois-hydxoxymathyX-propane to give the desired product Yield: 65% m.p.: 285*C (dec.) Elemental Analysis (%) CHIN Calculated: 26.32 2.68 50..55 5.58 Found: 26.21 2.72 50.31 5.53 TLC: (Silica Gel 60 F234i, Merck) Eluent: chci3/ch3oh/nh4oh 25% » 6/3/1 v/v/v. Rf « 0.X2 HPLC: Rt - 17.7 min. Titre » 98%(on the area) .Chromatographic conditions: as reported in Example 3. EKaKFI® 24 1,3-bis-i 3- (L-2-hydroxy-propionyl) amino-5-(N-methyl-N(D-l-deoxy-glucitol) ]aminocarbonyl-2,4,6-triiodo-benzoyl-amino ]-2,2-bis-hydroxymethyl~propane.
Following the procedure described in Example 2, 10 g of 3-(L-2-acetoxy-propionyl)amino-5-(N-methyl-N-iD-Xdeoxy-glucitol) ] aminocarbonyl-2 f, 4,6-triiodo-benzoylchloride (0.011 mol) in 50 ml of DMF are reacted with 1.19 g of l,3-diamino~2»2-bis-hydroxymethyl-propane (0.006 mol) and 4.94 g of' tributylamine (0.027 mol) in 20 ml of DMF. 11.5 g of the title compound are obtained. Yield: 58% Elemental Analysis
Claims (11)
1.CLAIMS 1- Symmetrical and asymmetrical 1,3-bis-(3-(mono- or poly-hydroxy) acy lamino-5-(mono- or· poly-hydroxvalkyl)aminocafbonyl-2,4,6-triiodo-benzoyl~amino]-hydroxy- or hydroxvalkyl-propanes ox general formula (I) wherein: R, R', which are the same or different, are a straight or branched mono- or poly-hydroxyalkyl C-j-Cg residue containing from 1 to 2 OB groups, Rp, R 9 , R 3 , which are the same or different, are H or CH 3 , R]l ,, Rj,, R 3 ,, which are the sane or differentiate 3 or CH~ 3, Alkyl(OH)is one of the groups of formula -CH(CH 2 OH)CH(OH)CH 2 OS, ~CH(CH 2 OB) ? , -CE 2 CHCOH)CH 2 OH, -CH^CCHOH) 4 CH 2 0H, or X is on® of the groups -CB(OH)- iP -CH(CH 2 03)-, -C(OH)(CH 9 0B)~ or -c(ch 2 oh) 2 -, A and B, may be the same or different, possible enantiomers, diastereoisomers and/or retainers thereof.
2. Compounds according to claim 1, where R^, r 3 represent hydrogen and the two residues A and B are equal.'
3. - Compounds according to claim 1, where R^, R^*,R 2 , R?·, R 3 , R 3 ', represent hydrogen and the two residues A and.3 are equal.
4. Compounds according to claim 1, where R,, R 2 ', Rg, R 3 ’ represent hydrogen, Alkyl(OH)represents the groups 1»3-dihydroxy-isopropyl or 2,3-dihydroxy-propyl, X represents the group -CH(OH)- and the two residues A and B are equal
5. A compound according to claims 1-4, selected in the group constituted by: - 1,3-bis-(3-(2-hydroxy-propionyl) amino-5-<1,3-dihydroxy-isopropyl )aminocarbonyl-2, 4,
6. -triiodobenzoy 1-amino3-2-hydroxy-propane1»3-bis-E 3-(L-2-hydroxy-propionyl)amino-5-(1,3dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodobenzoy 1-amino)-2-hydroxy-propane' 1,3-bis- (3-hydroxyacetylamino-5~(1,3-dihydroxyisopropyl)aminocarbonyl-2,4,6-triiodo-benzoy1amxno3-2,2-bis-hydroxymethy1-propane- 1 s 3-bis-(3-(L-2-hydroxy-propionyl)amino-5-(2,3dihydroxy-propyl)amxnocarbonyl-2,4,6-trxiodo-benzoy1-amino]-2-hydroxy-propane. 1.3- bis-(3-(L-2-hy dr oxy-propionyl)amino-5-(1,3,4trihydroxy-2-butyl5aminocarbonyl-2,4,6-triiodotaenzovl- amino 3-2-hydroxy-propane1- (3-(L—2—hydroxy—propionyl)amino-5-(1# 3-dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodo-benzoylamino )-3- (3-hydroxyacetylamin0-5- ¢2,3-dihydroxypropyl) aminocarbonyl-2,4,6-triiodo-benzov 1-amino J2- hydroxy-pr©pane1.3- bis-(3-hydroxyacetylasnino-5-C2,3-dihydroxy47 propyl)amxnocarbonyl-2,4„6-triiodo-benzoyl-aminoj2.2- bis-hydroxymethy1-propane 1.3- bis- [ 3-hydroxyacetylamino-5- (1,3,4-trihydroxy2-butyl) aminocarbonyl-2,4 g 6-triiodo-benzoylamino 3 -2,2-bis-hydroxyme thy 1-propane. 1.3- bis- [3-( L-2-hydroxy -propionyl} amino-5- [N-methyl-N-(1,3-dihydroxy-isopropyl) ]aminocarbonyl2, 4 , 6-triiodo-benzoyl~amino3 -2-hydroxy-propane. 1 3-bis- [3-( L-2-hydroxy-propxonyl) amino-5- [N-methyl-N- (2,3-dihydroxy-propyl) ] aminocarbonyl-2,4,6trixodo-benzoyl-amino ]-2-hydr oxy-propane. 1,3 —b is- [ N-methy 1-N- [3-( L-2-hydroxy-propxonyl) amxno-5- (1,3-dihydroxy-isopropyl) aminocarbonyl2,4,o-triiodo-benzoyl]amino 3-2-hydroxy-propane. 1.3- bis-[N-methy1-M-[3-(L-2-hydroxy-propionyl) amino-5- (2,3-dihydroxy-propyl)aminocarbonyl-2,4,6tr iiodo-benzoy 13 amino 3 -2-hydr oxy-propane. 1.3- bis- [ 3-hydroxyacetylamino-5- (1,3-dihydroxyisopropyl )aminocarbonyl-2,4,6-triiodo-benzoylamino 3-2-hydroxy-propane. 1,3-bis- [ 3-hydroxyacety lamino-5- (2,3-dihydroxypropyl ) aminocarbonyl-2,4,6-triiodo-benzoyl-amino32-hydroxy-propane. 1,3-bis- [ 3-hydroxyacetylamino~5- (1,3,4-trihydroxy2-butyl) aminocarbonyl-2,4,6-trxiodo-benzoylamxno 3-2-hydroxy-propane. 1,3-bis- [ 3-hydroxyacety lamino-5- [N-me thy 1-N- (1,3dihydroxy-isopropyl) 3 aminocarbonyl-2,4,6-tr iiodobenzoy 1-amino3-2-hydroxy-propaneX, 3-bis- [ 3-hydroxyacety lamino-5- (N-methyl-N- ('2,3dihydroxy-propyl) 3 aminocarbonyl-2,4,6-triiodofoen48 zoy1-amino3-2-hydroxy-propane1.3- bis-[N-methyl-N- (3-hydroxyacetvlamino-5- (1,3dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodobenzoyl] amino]-2-hydroxy-propane. S - X,3-bis-[N~methyl-N~i3-hydroxyacetylamino~5-(2,3dihydroxy-propyl) aminocarbonyl-2,4,6-triiodobenzoyl3amino3-2-hydroxy-propane. 1.3- bis- (3- (N-methyl-N-hydr oxy acetyl) amino-5- (1,3· dihydroxy-isopropyl) aminocarbonyl-2 , 4,6-tr iiodo10 benzoyl-amino 3-2-hydroxy-propane. 1.3- b is-(3-(N-me thyl-N-(L-2-hydroxy-propionyl)3amino-5-(1,3,4-trihydroxy-2-bntyl)aminocarbonyl2,, 4, 5-triiodo-benzoyl-amxno J -2-hydroxy-propane. 1.3- bis-(3-(N~methyl-N-(L-2-hydroxy-propionyl)315 amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl2,4 ,6-triiodo-benzoyl-amino3-2-hydroxy-propane. 1.3- bis-(3-[N-methyl-N-(I»-2-hydroxy-propionyl) 3amino-5- (2,3-dihydroxy-propyl) aminocarbonyl-2,4,6 triiodo-benzoyl-amino]-2-hydroxy-propane. 20 - l,3-bis-(3-(N-methyl-N-hydroxyacetyl)amino-5-(2,3 dihydroxy-propyl) aminocarbonyl-2, 4 ,6-triiodo-benzoy 1- amino 3 -2 -hydroxy-propane. 1.3- bis- (3- (N-me thy 1-N-hydroxy acetyl) amino-5(1,3,4-trihydroxy-2-butyl) aminocarbony1-2,4,62 5 triiodo-benzoyl-amino]-2-hydroxy-propane- l,3-bis-(3-iL-2-hydroacy-propi0nyl)amino-5-Cl,3-. dihydroxy-isopropyl)aminocarbonyl-2,4,6-triiodobenzoy 1-amino 3 -2,2-bis-hydr oxymethy 1-propane. - 1,3-bis-(3-(L-2-hydroxy-propionyl)amino-5-<2,33 0 dihydroxy-propyl) aminocarbonyl-2,4,6-tr iiodo-benzoy 1-amino ]-2,2-bis-hydroxyme thy 1-propane. 1 e 3-bis-(3-(L-2-hydroxy-propionyl)amino-5-(1,3,4trihydroxy-2-butyl) aminocarbonyl-2,4,6-triiodobenzoyl-amino ]-2,2-bis-hydroxymethyl-propane. 1,3 -b Is - [ 3 - [ N-me thy 1-S9- (L-2 -hydroxy-propionyl) ] amino-5-(1,3-dihydroxy-isopropyl)aminocarbonyl2, 4,6-triiodo-benzoyl-amino J-2,2-bis-hydroxyme thy1-pr©pane. 1.3- bis-[3-[N-raethy1-N-(L-2-hydroxy-propionyl)]amino-5-(2,3-dihydroxy-propyl)aminocarbonyl-2,4,6triiodo-benzoyl-amino J-2,2-bis-hydroxymethy1-propane. 1.3- bis-[ 3-[N-methy1-N- (L-2-hydroxy-propionyl) 3amino-5-(1,3,4-trihydroxy-2-butyl)aminocarbonyl2,4,6-triiodo-benzoyl~amino3~2,2-bis-hydroxymethyl-propane. 1.3- bis-(3-(N-methyl-N-hydroxyacetyl) amino-5-(1,3dihydroxy-isopropyl)aminocarbonyl-2,4„6-triiodobenzoyl-amino 3-2 ,2-bis-hydroxymethyl-propane1.3- bis-[3-(N-methyl-N-hydroxyacetyl) aminO-5-(2,3dihydroxy-propyl) aminocarbonyl-2,4,6-tr iiodo-benzoyl-amino 3-2,2-bis-hydroxymethyl-propane. 1.3- bis-[3-(N-methyl-N-hydroxyacetyl)amino-5(1,3,4-trihydroxy-2-butyl)aminocarbonyl-2,4,6triiodo-benzoyl-amino] -2,2-bis-hydroxymethy1propane. 1.3- bis-[3-(L-2-hydroxy-propionyl) amino-5-[Nmethyl-N- (D-l-deoxy-glucitol) 3 aminocarbonyl-2,4,6tr iiodo-benzoy 1-amino 3-2-hy dr oxy-propane. X,3-bis-[3-(L-2-hydroxy-propionyl)amino-5-[N-methy 1-N- (D-l-deoxy-glucitol)]aminocarbonyl-2,4,6triiodo-benzoyl-amino 3 -2,2-bis-hydroxymethyl-pro50 pane. 1- (3-hydroxyacetylamino-5- (1,3,4-trihydroxy-2-bu~ tyl)aminocarbony1-2,4,6-triiodo-benzoy1-amino3-3✓ [3-( L-2-hydroxy-propionyl)amino-5-(1,3-dihydroxy5 isopropyl) aminocarbony 1-2,4,6-t ri iodo-benzoylamino 3-2-hydroxy-propane. - 1-(3-(L-2-hydroxy-propionyl)amino-5- (1,3-dihy drosey-isopropyl) aminocarbonyl-2,4 e 6-triiodo-benzoy1amino 3-3-( 3-(L-2-hydroxy-propionyl) amino-5- (2,310 dihydroxy-propyl) aminocarbonyl-2,4„6-triiodobenzoy1-amino3-2-hydroxy-propane1-[3-(L-2-hydroxy-propionyl) amino-5-(X,3-dihydroxy-isopropyl) aminocar bony 1-2,4,6-triiodo-benzovlamin©3-3- (3-(L-2-hydroxy-propionyl) amino-5-(N-me15 thyl-N-(D~l~deoxy-gIueitol)]aminocarbony1-2,4,6triiodo-benzoy 1-amino ] -2-hydroxy-propane . - 1,3-bis-(N-methy X-N-[ 3-hydroxyacetylamino-5(1,3,4-trihydroxy-2-butyl) aminocarbonyl-2,4,6triiodo-benzoyl 3 amino ] -2-hydroxy-propane. 20 - 1,3-bis-(N-methy 1-N- [3-hydroxyacety lamino-5-(Nmethyl-N- (1,3-dihydroxy-isopropyl) 3 aminocarbonyl2,4, 6-triiodo-benzoyl 3 amino 3-2-hydroxy-propane» X, 3-bis-(N-methyl-N- (3-hydroxyacetylamino-5-(Nmethy 1-N- (D-l-fieoxy-glucitol) 3 aminocarbonyl-2,4,6 2 5 tri iodo-benzoyl 3 amino 3 -2-hydroxy-propane - 1,3-bis-(N-methyl-N-(3-(L-2-hydroxy-propionyl)amino-5- (2-hydroxy-ethy 1) aminocarbony 1-2,4,6triiodo-benzoyl3 amino 3-2-hydroxy-propane. 1,3-bis-(N-methyl-N-(3-(L-2~hydroxy-pxopionyli3 0 amino-5- (1,3,4-trihydroxy-2-butyl > aminocarbonyl2,4, 6-tr iiodo-benzoyl 3 amino 3-2-hydroxy-propane. SI - l,3-bis-CiS-me'thyl<-S-i3-CH-Methyl~ia:-,(L ! -.2-hyaroaypropionyl} }aminc^S-(2--hydro3ty-ethyl} aminocasSsonyl2 * 4 1 S-trSiodo-benzoyllamiaol—Z—hydroaqy-propaae. l,3^is-iN-methyl-S-i3-(N-met5ayl-M-(M-&ydr<3xy5 propionyl} }amino-S-(l, 3—dihydroxy-ispropyl} amiaocarhonyl-2, 4 , €-tr iiodo-beazqyl j amino 3 -2-hydroxypropane6. Process for the preparation of the l,3-feis-£3(mono- or poly-hydwsy) acy lamino-S—(mono- or poly10 hydroxyalkyl) aminocarbonyl-2,4,6-trix0do-toenzc(ylamiaol-hydxosy- or hydroxyalkyl-prcpaae of «general for— mula (I), according to claim 1 characterised in that a 1,3-diamino-hydroxy-or hydroxyalkyl-propane of general formula (Π) s^-HS-cs^x-ca^-sH-ag’· ' (nj IS wherein -S^' and Rg’ are H or X Orse groups -ca(ea}~, -caaic^OH)-, ~e ’· . wherein.: 30 R^, represent a or €3^, R^ is a straight or branched mono- * or poly-acy52 loxyalkyl C 1 -C 1 g residue containing from 3 to 13 atoms of C and from 1 to 2 lower acyloxy groups C 2 C 5 8 ' of formula -CB(CB 2 Oa)CHAlkyl(OH)g is one of· the groups -CH 9 (CHOH) 4 CH^OS, -CB^CH(OH)CH 2 OH, (0H)CH 7 0H, -CH 2 CH 9 0H, -CHiCH^OH) 2 , or in which the hydroxy groups may he protected preferably by acetalic or ketalic groups,, CO-Y is the residue of a mixed anhydride or, preferably, a halogenocarbonyl group, to give the product of general formula (17) (IV). wherein R„ and IU, R, f R fo) 1 , , R^ 8 , R 3 ', R^,, Alkyl(OR).^ 3 X have the previously described meaning and Rg may be R or R £i according to one of the following procedures: a) a compound of general formula (II) is reacted with a compound of general formula (III) in a molar ratio of 1:2 in a solvent and in the presence of a basic condensation agent to directly obtain a compound of formula (17) where Rg corresponds to a compound of formula (II), in which one of the two amino groups is protected by a suitable protective group, is reacted with a compound of formula (III) in a molar ratio of 1:1 in a solvent and in the presence of a basic condensation agent to ·obtain, after hydrolysis of the protective groups, the corresponding 1-(3-(mono- or polyhydroxyJacylamino-S-imono- ax’ poly-hvdroxyalkyl)amxnocarbonyl-2,4,6-triiiodo-benzoyl-amxno)-3amino-hydroxyalkyl derivative of formula (V) R 3 ‘ I NH (VS. IS wherein R, R^, been previously defined, and this compound (V) is subsequently reacted with a derivative of formula (XII) in the presence of a basic condensation agent to obtain the desired compound (XV) where R^ corresponds to R, then, the compound (IV) obtained through one of the synthetic methods a) or b) is transformed, by hydrolysis of the protective groups, into the corresponding compound of formula (I) and this last one, if the two R^ and R. · axe H, may be, if desired, N-methylated in an alkaline medium.
7. Process for the preparation of compounds of general formula (I)» where and Κ Ί ’ are CH 3 , characterized in that a compound of general formula (I), in which R^ and are hydrogen, is methylated in an alkaline solution by means of treatment with methyl halide, dimethyIsulphate, methylsulphonate, dimethylcarbonate .
8. Non-ionic X-ray contrast agents containing as an opacifying component at least one 1,3-bis-(3-(mono- or poly-hydroxy)acylaraino-5-(mono- or poly-hydroxyalkyl ) aminocarbonyl-2,4,6-triiodo-benzoy 1-amino ] hydroxy or hydroxyalkyl-propane according- to claims 1 5 to 5.
9. Compounds according to any one of claims 1 to 4 9 substantially as described herein by way of Example.
10. A process according to claim β or claim 7 substantially as described herein by way of Example.
11. Compounds prepared by the process of any of claims 6., 7 and
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| IT02208890A IT1245853B (en) | 1990-11-16 | 1990-11-16 | 1,3-BIS (3- (MONO OR POLYHYDROXY) ACYLAMINE-5- (MONO OR POLYHYDROXY-ALCHYL) AMINOCARBONYL-2,4,6-TRIIODE-BENZOYL-AMINO) -HYDROXY- OR HYDROXY-ALCHYL-PROPANE, THEIR METHOD OF PREPARATION AND ROENTGENOGRAPHIC CONTRAST MEANS THAT CONTAIN THEM |
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|---|---|---|---|---|
| FR2717799B1 (en) * | 1994-03-22 | 1996-07-19 | Guerbet Sa | Polyiodes compounds: preparation process; diagnostic composition. |
| DE60235423D1 (en) | 2001-12-20 | 2010-04-01 | Bone Support Ab | New bone mineral replacement |
| ATE430146T1 (en) | 2004-07-02 | 2009-05-15 | Bracco Imaging Spa | HIGH RELAXIVITY CONTRAST AGENT FOR USE IN MAGNETIC RESONANCE IMAGING (MRI), CONTAINING A CHELATING GROUP WITH POLYHYDROXYLATED SUBSTITUENTS |
| US7407647B2 (en) | 2005-12-07 | 2008-08-05 | Cordis Corporation | Organic radiographic contrasting agents for medical devices |
| US20070134163A1 (en) * | 2005-12-13 | 2007-06-14 | Zhao Jonathon Z | Radiographic contrasting agents and radio-opaque polymeric materials for medical devices |
| ES2396567T3 (en) * | 2006-02-14 | 2013-02-22 | Ge Healthcare As | Contrast agents |
| EP2178568B1 (en) | 2007-07-12 | 2014-07-02 | Ge Healthcare As | Contrast agents |
| JP2011500533A (en) | 2007-10-12 | 2011-01-06 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Contrast agent |
| EP2200971B1 (en) * | 2007-10-12 | 2013-04-24 | GE Healthcare AS | Contrast agents |
| WO2009047318A1 (en) | 2007-10-12 | 2009-04-16 | Ge Healthcare As | Contrast agents |
| JP2011500530A (en) * | 2007-10-12 | 2011-01-06 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Contrast agent |
| GB2453654A (en) * | 2007-10-12 | 2009-04-15 | Ge Healthcare As | A compound for use in X-ray contrast examinations |
| WO2009056555A1 (en) * | 2007-10-30 | 2009-05-07 | Ge Healthcare As | Contrast agents |
| US20100303734A1 (en) * | 2007-12-05 | 2010-12-02 | Veronique Morisson-Iveson | Contrast agents |
| WO2009097277A1 (en) * | 2008-02-01 | 2009-08-06 | Trustees Of Boston University | Cationic contrast agents and methods of use thereof |
| US20110021824A1 (en) * | 2009-07-21 | 2011-01-27 | Ge Healthcare As | Adsorptive purification method for iodixanol |
| WO2016079330A1 (en) | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for local drug release |
| WO2016123583A1 (en) | 2015-01-29 | 2016-08-04 | Theracell, Inc. | Demineralized bone fiber composition for use in minimally invasive surgery |
| MX2018014087A (en) | 2016-05-20 | 2019-06-10 | Univ Denmark Tech Dtu | Palpable marker composition. |
| US10639157B2 (en) | 2017-03-14 | 2020-05-05 | Theracell, Inc. | Demineralized bone fiber composition for use in minimally invasive surgery |
| CA3143104A1 (en) | 2019-06-12 | 2020-12-17 | Technical University Of Denmark | Dissacharide formulations for controlled drug release |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1491129A (en) * | 1975-06-04 | 1977-11-09 | Guerbet Sa | Iodo-benzene derivatives and an x-ray contrast medium containing them |
| CH626873A5 (en) * | 1977-03-28 | 1981-12-15 | Bracco Ind Chimica Spa | |
| US4584401A (en) * | 1983-10-20 | 1986-04-22 | Biophysica Foundation | Methods and compositions involving polyhydroxylated polyiodo non-ionic contrast media |
| DE3731542A1 (en) * | 1987-09-17 | 1989-03-30 | Schering Ag | NEW DICARBONIC ACID-BIS (3,5-DICARBAMOYL-2,4,6-TRIIOD-ANILIDE), METHOD FOR THE PRODUCTION THEREOF AND THESE CONTAINING X-RAY AGENTS |
-
1990
- 1990-11-16 IT IT02208890A patent/IT1245853B/en active IP Right Grant
-
1991
- 1991-11-11 IS IS3781A patent/IS3781A7/en unknown
- 1991-11-12 NZ NZ240566A patent/NZ240566A/en unknown
- 1991-11-14 IL IL10005491A patent/IL100054A/en not_active IP Right Cessation
- 1991-11-15 AT AT91919864T patent/ATE111441T1/en not_active IP Right Cessation
- 1991-11-15 WO PCT/EP1991/002151 patent/WO1992008691A1/en active IP Right Grant
- 1991-11-15 IE IE398691A patent/IE66460B1/en not_active IP Right Cessation
- 1991-11-15 JP JP3517985A patent/JP2977613B2/en not_active Expired - Fee Related
- 1991-11-15 ZA ZA919065A patent/ZA919065B/en unknown
- 1991-11-15 DK DK91919864.8T patent/DK0557345T3/en active
- 1991-11-15 MX MX9102103A patent/MX9102103A/en not_active IP Right Cessation
- 1991-11-15 DE DE0557345T patent/DE557345T1/en active Pending
- 1991-11-15 CA CA002096136A patent/CA2096136A1/en not_active Abandoned
- 1991-11-15 EP EP91919864A patent/EP0557345B1/en not_active Expired - Lifetime
- 1991-11-15 DE DE69104059T patent/DE69104059T2/en not_active Expired - Fee Related
- 1991-11-15 ES ES91919864T patent/ES2060415T3/en not_active Expired - Lifetime
- 1991-11-15 HU HU9301375A patent/HUT65652A/en unknown
- 1991-11-15 AU AU89253/91A patent/AU646119B2/en not_active Ceased
-
1993
- 1993-05-12 KR KR1019930701423A patent/KR930702281A/en not_active Application Discontinuation
-
1994
- 1994-02-28 GR GR930300134T patent/GR930300134T1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IT1245853B (en) | 1994-10-25 |
| DE69104059T2 (en) | 1995-02-02 |
| ZA919065B (en) | 1992-08-26 |
| WO1992008691A1 (en) | 1992-05-29 |
| CA2096136A1 (en) | 1992-05-17 |
| ATE111441T1 (en) | 1994-09-15 |
| NZ240566A (en) | 1994-02-25 |
| IT9022088A0 (en) | 1990-11-16 |
| IE913986A1 (en) | 1992-05-20 |
| AU646119B2 (en) | 1994-02-10 |
| IT9022088A1 (en) | 1992-05-17 |
| AU8925391A (en) | 1992-06-11 |
| DE69104059D1 (en) | 1994-10-20 |
| IL100054A0 (en) | 1992-08-18 |
| IS3781A7 (en) | 1992-05-17 |
| HU9301375D0 (en) | 1993-09-28 |
| DE557345T1 (en) | 1994-07-28 |
| IL100054A (en) | 1996-05-14 |
| EP0557345A1 (en) | 1993-09-01 |
| MX9102103A (en) | 1992-06-01 |
| JPH06504268A (en) | 1994-05-19 |
| EP0557345B1 (en) | 1994-09-14 |
| GR930300134T1 (en) | 1994-02-28 |
| HUT65652A (en) | 1994-07-28 |
| DK0557345T3 (en) | 1995-03-06 |
| JP2977613B2 (en) | 1999-11-15 |
| KR930702281A (en) | 1993-09-08 |
| ES2060415T3 (en) | 1994-11-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |