NO180297B - Nonionic iodinated compounds and contrast agents containing the same - Google Patents
Nonionic iodinated compounds and contrast agents containing the same Download PDFInfo
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- NO180297B NO180297B NO913403A NO913403A NO180297B NO 180297 B NO180297 B NO 180297B NO 913403 A NO913403 A NO 913403A NO 913403 A NO913403 A NO 913403A NO 180297 B NO180297 B NO 180297B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- 239000002872 contrast media Chemical class 0.000 title claims description 12
- -1 2,3-dihydroxypropyl Chemical group 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- WOMTYMDHLQTCHY-UHFFFAOYSA-N 3-methylamino-1,2-propanediol Chemical compound CNCC(O)CO WOMTYMDHLQTCHY-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N Methyl ethyl ketone Natural products CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 150000008424 iodobenzenes Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- YZSDZIUZNIOTQR-UHFFFAOYSA-N 1-(methylamino)propane-1,3-diol Chemical compound CNC(O)CCO YZSDZIUZNIOTQR-UHFFFAOYSA-N 0.000 description 1
- PQRPEYHKHZRSEK-UHFFFAOYSA-N 1-n,3-n-bis(1,3-dihydroxypropan-2-yl)-2,4,6-triiodo-1-n,3-n-dimethyl-5-[(2-propan-2-yl-1,3-dioxane-4-carbonyl)amino]benzene-1,3-dicarboxamide Chemical compound O1C(C(C)C)OCCC1C(=O)NC1=C(I)C(C(=O)N(C)C(CO)CO)=C(I)C(C(=O)N(C)C(CO)CO)=C1I PQRPEYHKHZRSEK-UHFFFAOYSA-N 0.000 description 1
- WLGYNCAVDBDTDP-UHFFFAOYSA-N 1-n,3-n-bis(1,3-dihydroxypropan-2-yl)-5-[[3-hydroxy-2-(hydroxymethyl)propanoyl]amino]-2,4,6-triiodo-1-n,3-n-dimethylbenzene-1,3-dicarboxamide Chemical compound OCC(CO)N(C)C(=O)C1=C(I)C(NC(=O)C(CO)CO)=C(I)C(C(=O)N(C)C(CO)CO)=C1I WLGYNCAVDBDTDP-UHFFFAOYSA-N 0.000 description 1
- XMXRYULKKLMYGH-UHFFFAOYSA-N 2,4,6-triiodo-5-[(2-propan-2-yl-1,3-dioxane-5-carbonyl)amino]benzene-1,3-dicarbonyl chloride Chemical compound C1OC(C(C)C)OCC1C(=O)NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I XMXRYULKKLMYGH-UHFFFAOYSA-N 0.000 description 1
- YMFOWIJFFPALOW-UHFFFAOYSA-N 2-(methylamino)propane-1,3-diol Chemical compound CNC(CO)CO YMFOWIJFFPALOW-UHFFFAOYSA-N 0.000 description 1
- YEOYYWCXWUDVCX-UHFFFAOYSA-N 2-iodobenzamide Chemical class NC(=O)C1=CC=CC=C1I YEOYYWCXWUDVCX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 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
- BAQCROVBDNBEEB-UBYUBLNFSA-N Metrizamide Chemical compound CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C(=O)N[C@@H]2[C@H]([C@H](O)[C@@H](CO)OC2O)O)=C1I BAQCROVBDNBEEB-UBYUBLNFSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000554 metrizamide Drugs 0.000 description 1
- 239000003690 nonionic contrast media Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører forbindelser som kan anvendes som kontrastmidler for radiografi. The present invention relates to compounds that can be used as contrast agents for radiography.
Oppfinnelsen vedrører også kontrastmidler inneholdende de samme forbindelser. The invention also relates to contrast agents containing the same compounds.
Jodbenzenforbindelser som inneholder flere'jodatomer i benzen-ringen, vanligvis 3 jodatomer pr benzenring, og forskjellige andre substituenter har i lengre tid vært anvendt som kontrastmidler. Disse andre substituenter er farmakologisk tålbare grupper som gjør at forbindelsene kan tilføres til mennesker og dyr. Generelt velges disse substituenter, på den ene side, for å gi forbindelsene passende oppløselighet i vann slik at de kan tilføres i vandig oppløsning og, på den annen side, for å gi disse forbindelser en toleranse som er til-strekkelig for deres anvendelse i humane organismer. Iodobenzene compounds containing several iodine atoms in the benzene ring, usually 3 iodine atoms per benzene ring, and various other substituents have for a long time been used as contrast agents. These other substituents are pharmacologically tolerable groups which enable the compounds to be administered to humans and animals. In general, these substituents are chosen, on the one hand, to give the compounds suitable solubility in water so that they can be administered in aqueous solution and, on the other hand, to give these compounds a tolerance sufficient for their use in humans organisms.
For dette formål er ikke-ioniske strukturer foreslått, dvs. jodbenzenderivater med ikke-ioniske substituenter. For this purpose, non-ionic structures have been proposed, i.e. iodobenzene derivatives with non-ionic substituents.
I patentet FR-A-2 053 037 ble således karbamoyljodbenzenfor-bindelser som totalt inneholder minst en N-hydroksyalkyl-gruppe og minst to hydroksygrupper foreslått. Thus, in the patent FR-A-2 053 037, carbamoyl iodobenzene compounds containing a total of at least one N-hydroxyalkyl group and at least two hydroxy groups were proposed.
En forbindelse som illustrerer denne gruppen er metrizamid som imidlertid har vist seg å ha begrenset stabilitet. A compound that illustrates this group is metrizamide which, however, has been shown to have limited stability.
I EPO patentsøknad nr 89 401 509.8 ble det foreslått ikke-ioniske forbindelser som tolereres godt av den humane organ-isme og som utviser god stabilitet i vandig oppløsning. Disse forbindelser har formelen: In EPO patent application no. 89 401 509.8, non-ionic compounds were proposed which are well tolerated by the human organism and which exhibit good stability in aqueous solution. These compounds have the formula:
hvori in which
R1 er en gruppe med formel R1 is a group of formula
hvori in which
R5 er valgt fra C1-C4 alkyl, C1-C4 hydroksyalkyl eller C1-<C>4R5 is selected from C1-C4 alkyl, C1-C4 hydroxyalkyl or C1-<C>4
polyhydroksyalkyl, polyhydroxyalkyl,
R6 er valgt fra hydrogen, C1-C4 alkyl, Cx- C4 hydroksyalkyl eller C1-C4 polyhydroksyalkyl, R6 is selected from hydrogen, C1-C4 alkyl, Cx-C4 hydroxyalkyl or C1-C4 polyhydroxyalkyl,
eller en gruppe med formelen or a group with the formula
hvori in which
R7 er valgt fra Cx-C4 hydroksyalkyl eller C1-C4 polyhydroksyalkyl , R7 is selected from Cx-C4 hydroxyalkyl or C1-C4 polyhydroxyalkyl,
R8 er valgt fra hydrogen eller C^ C^ alkyl, R 8 is selected from hydrogen or C 1 -C 4 alkyl,
R2 er valgt fra hydrogen, C1-C4 hydroksyalkyl eller C1-C4R2 is selected from hydrogen, C1-C4 hydroxyalkyl or C1-C4
polyhydroksyalkyl, polyhydroxyalkyl,
R3 er valgt fra hydrogen eller C-^-C^ alkyl, og R 3 is selected from hydrogen or C 1 -C 4 alkyl, and
R4 er valgt fra hydrogen, C^-C^ alkyl, C1-C4 hydroksyalkyl R 4 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl
eller C-^- C^ polyhydroksyalkyl. or C 1 -C 3 polyhydroxyalkyl.
Formålet med den foreliggende oppfinnelse er å tilveiebringe nye forbindelser som tilhører gruppen av forbindelser med formel I, som er kjennetegnet ved både god stabilitet og god oppløselighet i vandig medier. The purpose of the present invention is to provide new compounds belonging to the group of compounds with formula I, which are characterized by both good stability and good solubility in aqueous media.
Forbindelsene i henhold til den foreliggende oppfinnelse har den følgende generelle formel: The compounds according to the present invention have the following general formula:
hvori R velges fra 2,3-dihydroksypropyl og 1,3-dihydroksy-2-propyl. wherein R is selected from 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
En av forbindelsene i henhold til den foreliggende oppfinnelse er 5-[3-hydroksy-2-(hydroksymetyl)-propionamido]-N,N'-dimetyl-N,N'-bis-(2,3-dihydroksypropyl)-2,4,6-trijodisoftalamid, dvs. forbindelsen med formelen: One of the compounds according to the present invention is 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2, 4,6-triiododisophthalamide, i.e. the compound with the formula:
Den andre forbindelse i henhold til den foreliggende oppfinnelse er 5-[3-hydroksy-2-(hydroksymetyl)-propionamido]-N,N'-dimetylN,N'-bis-(1,3-dihydroksy-2-propyl)-2,4,6-trijodiso-ftalamid, med formelen: The second compound according to the present invention is 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethylN,N'-bis-(1,3-dihydroxy-2-propyl)- 2,4,6-triiododiso-phthalamide, with the formula:
Disse formler dekker ikke bare racematene men også alle de stereoisomerer som er forbundet med tilstedeværelsen av asym-metrisk karbon og med hindring av rotasjon av visse bindinger som skyldes den steriske hindring tilveiebragt av jodatomene. These formulas cover not only the racemates but also all the stereoisomers associated with the presence of asymmetric carbon and with the hindrance of rotation of certain bonds due to the steric hindrance provided by the iodine atoms.
Forbindelsen med formel A er uventet kjennetegnet ved en bedre oppløselighet i et vandig medium enn forbindelsen i eks. 1 i den ovennevnte EPO patentsøknad, nemlig 5-[3-hydroksy-2- The compound with formula A is unexpectedly characterized by a better solubility in an aqueous medium than the compound in ex. 1 in the above-mentioned EPO patent application, namely 5-[3-hydroxy-2-
(hydroksymetyl)-N-(2,3-dihydroksypropyl)propionamido]-N',N"-bis-(2-hydroksyetyl)-2,4,6-trijodisoftalamid. (hydroxymethyl)-N-(2,3-dihydroxypropyl)propionamido]-N',N"-bis-(2-hydroxyethyl)-2,4,6-triiododisophthalamide.
Videre har forbindelsene i henhold til den foreliggende oppfinnelse den fordel sammenlignet med forbindelsen i eks. 1 i den ovennevnte patentsøknad, at de lettere kan oppnås ved at de ikke krever et endelig N-alkyleringstrinn som gir problemer i forbindelse med rensing ved fremstilling i industriell måle-stokk . Furthermore, the compounds according to the present invention have the advantage compared to the compound in ex. 1 in the above-mentioned patent application, that they can be obtained more easily in that they do not require a final N-alkylation step which causes problems in connection with purification during production on an industrial scale.
Forbindelsene i følge den foreliggende oppfinnelse kan oppnås i henhold til en prosedyre som omfatter at: The compounds according to the present invention can be obtained according to a procedure which includes that:
a) et diacylklorid med formel: a) a diacyl chloride of formula:
hvori in which
R' er en -CH-(CH2OH)2 gruppe hvis hydroksygrupper er beskyttet, reageres med et amin valgt fra 1-(N-metylamino)-propan-2,3-diol og 2-(N-metylamino)-propan-1,3-diol, for fremstilling av en forbindelse med formel: R' is a -CH-(CH2OH)2 group whose hydroxy groups are protected, is reacted with an amine selected from 1-(N-methylamino)-propane-2,3-diol and 2-(N-methylamino)-propane-1 ,3-diol, for the preparation of a compound of formula:
og and
b) at beskyttelsesgruppene fjernes fra R'-gruppen. b) that the protecting groups are removed from the R' group.
Forbindelsene med formel II er beskrevet i FR-A-2 632 304. The compounds of formula II are described in FR-A-2 632 304.
Den foreliggende oppfinnelse vedrører også kontrastmidler som inneholder minst en av forbindelsene i henhold til den foreliggende oppfinnelse. The present invention also relates to contrast media containing at least one of the compounds according to the present invention.
Disse kontrastmidler anvendes i mennesker og dyr for radio-logiske formål. These contrast agents are used in humans and animals for radiological purposes.
De foretrukne farmasøytiske former av kontrastmidlene i henhold til den foreliggende oppfinnelse omfatter vandige oppløsninger av forbindelsene. The preferred pharmaceutical forms of the contrast agents according to the present invention comprise aqueous solutions of the compounds.
De vandige oppløsninger inneholder vanligvis totalt fra 5 til 100 g forbindelse i henhold til oppfinnelsen pr 100 ml og det injiserbare volum av slike oppløsninger varierer vanligvis fra 1 til 1000 ml. The aqueous solutions usually contain a total of from 5 to 100 g of compound according to the invention per 100 ml and the injectable volume of such solutions usually varies from 1 to 1000 ml.
De vandige oppløsninger av forbindelsene i henhold til oppfinnelsen kan også inneholde visse tilsetningsstoffer som: The aqueous solutions of the compounds according to the invention may also contain certain additives such as:
- natriumklorid i konsentrasjoner mellom 0,1 og 10 mM - sodium chloride in concentrations between 0.1 and 10 mM
- dinatrium EDTA i konsentrasjoner mellom 0,1 og 2 mM - disodium EDTA in concentrations between 0.1 and 2 mM
- natriumcitrat i konsentrasjoner mellom 0,1 og 10 mM - sodium citrate in concentrations between 0.1 and 10 mM
- heparin i doser mellom 10 og 100 enheter pr 100 ml oppløsning. - heparin in doses between 10 and 100 units per 100 ml of solution.
Disse-forbindelser kan tilføres på alle vanlig anvendte måter som anvendes for joderte ikke-ioniske kontrastmidler. De kan således tilføres enteralt eller parenteralt (intravenøst eller intra-arterielt, skyggelegge hulrom) og spesielt inn i subar-aknoidalrommet. These compounds can be added in all commonly used ways that are used for iodinated non-ionic contrast media. They can thus be administered enterally or parenterally (intravenous or intra-arterial, shadowing cavities) and especially into the subar-achnoid space.
Et eksempel på middelet i henhold til den foreliggende oppfinnelse er gitt i det etterfølgende. An example of the agent according to the present invention is given below.
Blanding Mixture
Forbindelse A i henhold til oppfinnelsen 65 g Compound A according to the invention 65 g
Vann for injiserbart preparat q.s. 100 ml Water for injectable preparation q.s. 100 ml
De etterfølgende eksempler illustrerer fremstillingen av forbindelsene i henhold til oppfinnelsen. The following examples illustrate the preparation of the compounds according to the invention.
Eksempel 1 Example 1
Fremstilling av 5-[ 3- hydroksy- 2-( hydroksymetyl)- propionamido1 - N, N'- dimetyl- N, N'- bis-( 2, 3- dihydroksypropyl)- 2, 4, 6- trii odisoftalamid. a) Fremstilling av [2-isopropyl-l,3-dioksan-5-karboksamido]-N,N'-dimetyl-N,N'-bis-(2,3-dihydroksypropyl)-2,4,6-trijodiso-ftalamid. 74 g (98 mmol) 5-[2-isopropyl-l,3-dioksan-5-karboksamido]-2,4,6-trijodisoftaloyl-diklorid suspenderes i 300 ml isopropanol som inneholder 41 ml (294 mmol) trietylamin. 31 g (295 mmol) N-metyl-aminopropan-2,3-diol tilsettes dråpevis. Blandingen omrøres i 12 timer ved romtemperatur. Trietylaminhydrokloridet fjernes ved filtrering. Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-propionamido-1-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triodisophthalamide. a) Preparation of [2-isopropyl-1,3-dioxane-5-carboxamido]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoiso- phthalamide. 74 g (98 mmol) of 5-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiododisophthaloyl dichloride are suspended in 300 ml of isopropanol containing 41 ml (294 mmol) of triethylamine. 31 g (295 mmol) of N-methyl-aminopropane-2,3-diol are added dropwise. The mixture is stirred for 12 hours at room temperature. The triethylamine hydrochloride is removed by filtration.
Filtratet avdampes til tørrhet, og resten tas opp i vann og elueres fra 0H- harpiks IRA 67. The filtrate is evaporated to dryness, and the residue is taken up in water and eluted from OH resin IRA 67.
Etter avdamping renses produktet ved at det føres gjennom silanisert silika (Kieselgel 60 Merck) med vann som elueringsmiddel. After evaporation, the product is purified by passing it through silanized silica (Kieselgel 60 Merck) with water as eluent.
Etter ^avdamping til tørrhet oppnås 60 g av et hvitt pulver i et utbytte på 68,5 %. After evaporation to dryness, 60 g of a white powder are obtained in a yield of 68.5%.
Jodbestemmelse: 96,4 % Iodine determination: 96.4%
HPLC renhet: 97 % Hypersil CB 25 cm 5 um HPLC purity: 97% Hypersil CB 25 cm 5 µm
NaH2P04 0,01 M' 60 NaH 2 PO 4 0.01 M' 60
Metanol 40 Methanol 40
TLC SiOo, Rf. 0,12 TLC SiO, Rf. 0.12
0,25 0.25
0,30 0,36 0.30 0.36
Elueringsmiddel CHC13 55, MeOH 30, NH3H20 10 Eluent CHC13 55, MeOH 30, NH3H20 10
NMR (DMSO) <1>H 200 MHz NMR (DMSO) <1>H 200 MHz
0,9 ppm (dublett) CH3 (6H); 2,8 ppm (singlett) N-CH3 (3H); 3 ppm (singlett) N-CH3 (3H) ; 3,3 ppm (multiplett) N-CH2 og CH (5H) ; 3,5-3,9 ppm (multiplett) CH2 og CH (8H); 4,3 ppm (kvadruplett) CH (3H); 4,6 ppm (triplett) OH (2H); 4,7 ppm (dublett) OH (2H); 10,2 ppm (forstørret multiplett) NH (1H). b) Fremstilling av 5-[3-hydroksy-2-(hydroksymetyl)-propionamido ]-N,N'-dimetyl-N,N'-bis-(2,3-dihydroksypropyl)-2,4 , 6-trij odisoftalamid. 0.9 ppm (doublet) CH3 (6H); 2.8 ppm (singlet) N-CH3 (3H); 3 ppm (singlet) N-CH3 (3H) ; 3.3 ppm (multiplet) N-CH2 and CH (5H); 3.5-3.9 ppm (multiplet) CH2 and CH (8H); 4.3 ppm (quadruplet) CH (3H); 4.6 ppm (triplet) OH (2H); 4.7 ppm (doublet) OH (2H); 10.2 ppm (enlarged multiplet) NH (1H). b) Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triodisophthalamide .
45 g (50,6 mmol) av forbindelsen beskrevet i a) oppløses i 45 g (50.6 mmol) of the compound described in a) are dissolved in
101 ml (10 ekv.) 5 N saltsyre. Blandingen omrøres i 12 timer ved romtemperatur. Oppløsningen filtreres og avdampes til tørrhet. Det oppnådde faststoff tas opp i 100 ml etyleter og avfiltreres deretter og elueres fra silanisert silika (Kieselgel 60 Merck) med vann. Etter avdamping til tørrhet oppnås 38 g av et hvitt pulver. 101 ml (10 equiv.) of 5 N hydrochloric acid. The mixture is stirred for 12 hours at room temperature. The solution is filtered and evaporated to dryness. The solid obtained is taken up in 100 ml of ethyl ether and then filtered off and eluted from silanized silica (Kieselgel 60 Merck) with water. After evaporation to dryness, 38 g of a white powder are obtained.
Utbytte = 90 % Yield = 90%
Jodbestemmelse: 98,3 % Iodine determination: 98.3%
HPLC renhet: 98 % Hypersil C8 25 cm 5 |lm HPLC purity: 98% Hypersil C8 25 cm 5 µm
NaH2P04 0,01 M 95 NaH 2 PO 4 0.01 M 95
MeOH 5 MeOH 5
TLC SiQ2, Rf. 0,56 TLC SiQ2, Rf. 0.56
0, 63 0.63
0,67 0.67
Elueringsmiddel CHC13 55, MeOH 30, NH3H20 10 Eluent CHC13 55, MeOH 30, NH3H20 10
NMR (DMSO) XH 200 MHz NMR (DMSO) 1 H 200 MHz
2,7 ppm (multiplett) CH (1H); 2,85 ppm (utvidet singlett) N-CH3 (3H); 3,08 (dårlig oppløst dublett) N-CH3 (3H); 3,10-3,35 ppm (multiplett) N-CH2; 3,45 ppm (kvadruplett) CH2 (4H); 2.7 ppm (multiplet) CH (1H); 2.85 ppm (extended singlet) N-CH3 (3H); 3.08 (poorly resolved doublet) N-CH3 (3H); 3.10-3.35 ppm (multiplet) N-CH2; 3.45 ppm (quadruplet) CH2 (4H);
3,6-4 ppm (multiplett) OH (6H); 9,9 ppm (multiplett) NH (1H). 3.6-4 ppm (multiplet) OH (6H); 9.9 ppm (multiplet) NH (1H).
Eksempel 2 Example 2
Fremstilling av 5-[ 3- hydroksy- 2-( hydroksymetyl)- propionamido1 -- N, N'- dimetyl- N, N'- bis-( 1, 3- dihydroksy- 2- propyl)- 2, 4, 6- trijod-isoftalamid. a) Fremstilling av [2-isopropyl-l,3-dioksan-6-karboksamido]-N,N'-dimetyl-N,N'-bis-(1,3-dihydroksy-2-propyl)-2,4,6-trijod-isoftalamid. Preparation of 5-[ 3- hydroxy- 2-( hydroxymethyl)- propionamido1 -- N, N'- dimethyl- N, N'- bis-( 1, 3- dihydroxy- 2- propyl)- 2, 4, 6- triiodo-isophthalamide. a) Preparation of [2-isopropyl-1,3-dioxane-6-carboxamido]-N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4, 6-triiodo-isophthalamide.
1,46 g (13,9 mmol) N-metyl-aminopropan-1,3-diol (syntetisert i henhold til EPO patentsøknad EP-A-025 083 innsendt av EPROVA A.G.) oppløses i en blanding bestående av 20 ml N,N-dimetyl-acetamid og 2 ml (114,4 mmol) trietylamin. 3,5 g (4,65 mmol) 5-(2-isopropyl-l,3-dioksan-5-karboksamido)-2,4,6-trijodiso-ftaloyldiklorid tilsettes i porsjoner. Blandingen omrøres i 3 timer ved 30°C og deretter i 12 timer ved romtemperatur. Trietylaminhydrokloridet fjernes ved filtrering. Filtratet avdampes til tørrhet og resten krystalliseres i en blanding bestående av 20 ml isopropanol og 200 ml etyleter. Etter filtrering og tørking oppnås 3,6 g av et hvitt pulver i et utbytte på 87 %. 1.46 g (13.9 mmol) of N-methyl-aminopropane-1,3-diol (synthesized according to EPO patent application EP-A-025 083 submitted by EPROVA A.G.) is dissolved in a mixture consisting of 20 ml of N,N -dimethylacetamide and 2 ml (114.4 mmol) of triethylamine. 3.5 g (4.65 mmol) of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodoisophthaloyl dichloride are added in portions. The mixture is stirred for 3 hours at 30°C and then for 12 hours at room temperature. The triethylamine hydrochloride is removed by filtration. The filtrate is evaporated to dryness and the residue is crystallized in a mixture consisting of 20 ml of isopropanol and 200 ml of ethyl ether. After filtration and drying, 3.6 g of a white powder are obtained in a yield of 87%.
TLC SiQ2, Rf. 0,16 TLC SiQ2, Rf. 0.16
0,28 0.28
Elueringsmiddel: toluen 60 - metyletylketon 35 - Eluent: toluene 60 - methyl ethyl ketone 35 -
maursyre 25. formic acid 25.
NMR (DMSO) <X>H200 MHz NMR (DMSO) <X>H 200 MHz
0,9 ppm (dublett) CH3 (6H); 1,7 ppm (multiplett) CH (1H); 2,7 ppm (singlett) N-CH3 (3H)Z isomer; 2,9 9 ppm (singlett) N-CH3 (3H) E isomer; 3,4-4 ppm (multiplett) CH, CH2 (15H); 4,8 ppm (multiplett) CH2OH (4H); 10,2 ppm (multiplett) NH (1H). b) Fremstilling av 5-[3-hydroksy-2-(hydroksylmetyl)-propionamido] -N,N'-dimetyl-N,N'-bis-(1,3-dihydroksy-2-propyl)-2,4,6-trij odisoftalamid. 0.9 ppm (doublet) CH3 (6H); 1.7 ppm (multiplet) CH (1H); 2.7 ppm (singlet) N-CH3 (3H)Z isomer; 2.9 9 ppm (singlet) N-CH3 (3H) E isomer; 3.4-4 ppm (multiplet) CH, CH2 (15H); 4.8 ppm (multiplet) CH2OH (4H); 10.2 ppm (multiplet) NH (1H). b) Preparation of 5-[3-hydroxy-2-(hydroxylmethyl)-propionamido]-N,N'-dimethyl-N,N'-bis-(1,3-dihydroxy-2-propyl)-2,4, 6-trij odisophthalamide.
3 g (3,4 mmol) av forbindelsen beskrevet i a) oppløses i 3 g (3.4 mmol) of the compound described in a) are dissolved in
10 ml (15 ekv.) 5 N saltsyre. Blandingen omrøres i 3 timer ved 45°C og deretter i 12 timer ved romtemperatur. Opp-løsningen avdampes til tørrhet. Den oppnådde rest tas opp i 50 ml etyleter, avfiltreres og oppløses deretter i 50 ml vann før den elueres fra en H+ harpiks (IRN 77) og en OH- harpiks (IRA 68). Etter avdamping til tørrhet oppnås 1,7 g av et hvitt pulver i et utbytte på 60,7 %. 10 ml (15 equiv.) of 5 N hydrochloric acid. The mixture is stirred for 3 hours at 45°C and then for 12 hours at room temperature. The solution is evaporated to dryness. The obtained residue is taken up in 50 ml of ethyl ether, filtered off and then dissolved in 50 ml of water before being eluted from an H+ resin (IRN 77) and an OH- resin (IRA 68). After evaporation to dryness, 1.7 g of a white powder is obtained in a yield of 60.7%.
Jodrenhet: 98,4 % Iodine purity: 98.4%
TLC SiQ2, Rf. 0,2 6 TLC SiQ2, Rf. 0.2 6
0,33 0.33
0,45 0.45
Elueringsmiddel: butanol 50, vann 25, eddiksyre 11. Eluent: butanol 50, water 25, acetic acid 11.
NMR (DMSO) <1>H 200 MHz NMR (DMSO) <1>H 200 MHz
2,7 ppm (utvidet singlett) N-CH3 (3H); Z'isomer; 3 ppm (utvidet singlett) N-CH3 (3H); E isomer; 3,3-4,05 ppm (dårlig oppløst multiplett) CH, CH2OH (15H); 4,45 ppm (dårlig oppløst multiplett) CH20H (6H); 9,8 ppm (multiplett) NH (1H). 2.7 ppm (extended singlet) N-CH3 (3H); Z' isomer; 3 ppm (extended singlet) N-CH3 (3H); E isomer; 3.3-4.05 ppm (poorly resolved multiplet) CH, CH2OH (15H); 4.45 ppm (poorly resolved multiplet) CH 2 OH (6H); 9.8 ppm (multiplet) NH (1H).
NMR (DMSO)<13> C 200 MHz. NMR (DMSO)<13> C 200 MHz.
145 ppm (CA1-NH); 100-98-90 ppm (CAr-I); 61-57-52 ppm (C-H); 59.1-59.9 ppm (CH2-0H); 32.8-30.1 ppm (CH3-N). 145 ppm (CA1-NH); 100-98-90 ppm (CAr-I); 61-57-52 ppm (C-H); 59.1-59.9 ppm (CH2-OH); 32.8-30.1 ppm (CH3-N).
Claims (8)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9000106A FR2656865B1 (en) | 1990-01-05 | 1990-01-05 | NON-IONIC IODINE COMPOUND, PROCESS FOR PREPARING THE SAME, AND CONTRAST PRODUCT CONTAINING THE SAME. |
| PCT/FR1990/000969 WO1991009836A1 (en) | 1990-01-05 | 1990-12-28 | Nonionic iodinated compounds, method for preparing them, and contrast products containing same |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO913403L NO913403L (en) | 1991-08-30 |
| NO913403D0 NO913403D0 (en) | 1991-08-30 |
| NO180297B true NO180297B (en) | 1996-12-16 |
| NO180297C NO180297C (en) | 1997-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO913403A NO180297C (en) | 1990-01-05 | 1991-08-30 | Nonionic iodinated compounds and contrast agents containing the same |
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| EP (1) | EP0437144B1 (en) |
| JP (1) | JP2529032B2 (en) |
| KR (1) | KR100194506B1 (en) |
| AT (1) | ATE114639T1 (en) |
| CA (1) | CA2050334C (en) |
| CZ (1) | CZ283986B6 (en) |
| DE (1) | DE69014581T2 (en) |
| DK (1) | DK0437144T3 (en) |
| ES (1) | ES2067710T3 (en) |
| FI (1) | FI102746B1 (en) |
| FR (1) | FR2656865B1 (en) |
| GR (1) | GR3015183T3 (en) |
| HK (1) | HK1006019A1 (en) |
| HU (1) | HUT59079A (en) |
| IE (1) | IE65329B1 (en) |
| IL (1) | IL96812A (en) |
| NO (1) | NO180297C (en) |
| NZ (1) | NZ236675A (en) |
| PL (1) | PL165683B1 (en) |
| PT (1) | PT96410B (en) |
| RO (1) | RO108559B1 (en) |
| SK (1) | SK279646B6 (en) |
| TR (1) | TR24944A (en) |
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| FR2687669B1 (en) * | 1992-02-24 | 1997-12-19 | Guerbet Sa | COMPOUNDS FOR USE IN CONTRAST PRODUCTS FOR RADIOGRAPHY. |
| IT1256163B (en) * | 1992-10-27 | 1995-11-29 | Zambon Spa | PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF THE ORGANIC SYNTHESIS |
| IT1283319B1 (en) * | 1996-03-29 | 1998-04-16 | Zambon Spa | PROCESS FOR THE PREPARATION OF A USEFUL INTERMEDIATE IN THE SYNTHESIS OF HYDURATED CONTRAST MEDIA |
| PT108524B (en) | 2015-06-02 | 2017-12-15 | Hovione Farmaciência S A | PROCESS FOR THE PREPARATION OF USEFUL INTERMEDIARIES IN THE PREPARATION OF NON-IONIC CONTRACTING AGENTS |
| CN108947959B (en) * | 2017-05-27 | 2022-09-20 | 正大天晴药业集团股份有限公司 | Preparation method of non-ionic iodine contrast agent intermediate |
| CN110903275A (en) * | 2018-09-14 | 2020-03-24 | 苏州科伦药物研究有限公司 | Process for producing iobitridol, intermediate therefor, and process for producing the same |
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| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| DE3429949A1 (en) * | 1984-08-10 | 1986-02-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Novel non-ionic 2,4,6-triiodoisophthalic acid bisamides, process for the preparation thereof and the use thereof as X-ray contrast media |
| IL90326A (en) * | 1988-06-02 | 1993-05-13 | Guerbet Sa | Non-ionic triiodobenzene compounds and contrast media containing them |
-
1990
- 1990-01-05 FR FR9000106A patent/FR2656865B1/en not_active Expired - Fee Related
- 1990-12-20 SK SK6482-90A patent/SK279646B6/en unknown
- 1990-12-20 CZ CS906482A patent/CZ283986B6/en not_active IP Right Cessation
- 1990-12-26 AT AT90403770T patent/ATE114639T1/en not_active IP Right Cessation
- 1990-12-26 DE DE69014581T patent/DE69014581T2/en not_active Expired - Lifetime
- 1990-12-26 ES ES90403770T patent/ES2067710T3/en not_active Expired - Lifetime
- 1990-12-26 EP EP90403770A patent/EP0437144B1/en not_active Expired - Lifetime
- 1990-12-26 DK DK90403770.2T patent/DK0437144T3/en active
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- 1990-12-28 CA CA002050334A patent/CA2050334C/en not_active Expired - Lifetime
- 1990-12-28 HU HU912860A patent/HUT59079A/en unknown
- 1990-12-28 WO PCT/FR1990/000969 patent/WO1991009836A1/en active IP Right Grant
- 1990-12-28 RO RO148263A patent/RO108559B1/en unknown
- 1990-12-28 KR KR1019910701024A patent/KR100194506B1/en not_active IP Right Cessation
-
1991
- 1991-01-03 PT PT96410A patent/PT96410B/en not_active IP Right Cessation
- 1991-01-04 JP JP3052354A patent/JP2529032B2/en not_active Expired - Lifetime
- 1991-01-04 NZ NZ236675A patent/NZ236675A/en unknown
- 1991-01-04 PL PL91288603A patent/PL165683B1/en not_active IP Right Cessation
- 1991-01-04 IE IE3591A patent/IE65329B1/en not_active IP Right Cessation
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- 1991-01-18 TR TR91/0009A patent/TR24944A/en unknown
- 1991-08-30 NO NO913403A patent/NO180297C/en not_active IP Right Cessation
- 1991-09-02 FI FI914114A patent/FI102746B1/en active
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1995
- 1995-02-27 GR GR940403887T patent/GR3015183T3/en unknown
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1998
- 1998-06-10 HK HK98105100A patent/HK1006019A1/en not_active IP Right Cessation
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