DE1467994A1 - X-ray contrast media - Google Patents
X-ray contrast mediaInfo
- Publication number
- DE1467994A1 DE1467994A1 DE19651467994 DE1467994A DE1467994A1 DE 1467994 A1 DE1467994 A1 DE 1467994A1 DE 19651467994 DE19651467994 DE 19651467994 DE 1467994 A DE1467994 A DE 1467994A DE 1467994 A1 DE1467994 A1 DE 1467994A1
- Authority
- DE
- Germany
- Prior art keywords
- triiodobenzoyl
- acid
- ray contrast
- radical
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000002872 contrast media Substances 0.000 title claims description 10
- 229940039231 contrast media Drugs 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 7
- -1 alkylene radical Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 239000002253 acid Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 229960002449 glycine Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000013189 cholangiography Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ASKVWXSOWXHYFI-UHFFFAOYSA-N 4-amino-2,5,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(I)=C(C(O)=O)C(I)=C1C(O)=O ASKVWXSOWXHYFI-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000631130 Chrysophyllum argenteum Species 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- DNPKPPNVNJMQFQ-UHFFFAOYSA-N carbonic acid;chloroform Chemical compound OC(O)=O.ClC(Cl)Cl DNPKPPNVNJMQFQ-UHFFFAOYSA-N 0.000 description 1
- 150000004653 carbonic acids Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- 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
Landscapes
- 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)
Description
Röntgenkontrastmittel Gegenstand der vorliegenden Erfindung sind Röntgenkontrastmit@@l, die dadurch gekennzeichnet ind, daß sie Verbindungen der all@@@ rneinen Formel in der R1 und R2 Wasserstoff oder eine Alkylgruppe, @ie durch @ine Alkoxy- oder Hydroxylgruppe zubstituiert sein kann, wobei bei@@ Recto gleich oder verschie@en sein können, R3 Wasserstoff, ei@@@ gesättigten oder ungesättigten Kohlenwasserstoffreat aliphati@@h@@, araliphatischer oder aromatischer Natur mit maximal 8 C-Atome@, der Hydroxy- oder Alkoxygruppen enthalten kann, oder den α-Furancmethylrest, X einen Methylenrest oder einen gegebene@falls verzweigten Alkylenreat mit maximal 6 Kohlenstoffatomen und Y tln Wasserstoffatom, einen Methyl- oder Äthylrest oder den Rest e@@er nichttosieohen anorganischctt oder oronischen} Hase bedeuten, enthalten Beaondero bevorzugt aind dabei Yerbldungen, in de@@n X einen Methylen-, Äthylen- oder Isopropylenrest und R3 einen nisderen Alkylrest, einen Allylrest oder einen 3-Methoxyprepylrest darstellt.X-ray contrast media The present invention relates to X-ray contrast media which are characterized in that they contain compounds of the formula in which R1 and R2 are hydrogen or an alkyl group, @ie can be substituted by an alkoxy or hydroxyl group, where @@ Recto can be the same or different, R3 hydrogen, ei @@@ saturated or unsaturated hydrocarbons creat aliphati @@ h @@, araliphatic or aromatic nature with a maximum of 8 carbon atoms @, which can contain hydroxyl or alkoxy groups, or the α-furancmethyl radical, X is a methylene radical or a given @ if branched alkyleneal with a maximum of 6 carbon atoms and Y tln hydrogen atom, a Methyl or ethyl radical or the radical e @@ er non-inorganischctt or oronic} rabbits, Beaondero preferably contain aind thereby Yerbldungen, in de @@ n X a methylene, ethylene or isopropylene radical and R3 a lower alkyl radical, an allyl radical or a Represents 3-methoxyprepyl radical.
Es wurde gefenden, daß sich die neuen Verbindungen gemäß Formel I infolge ihrer sehr niedrigen Toxizität und gluten Verträglichkeit ausgezeichnet für die Verwendung in der Röntgendiagnostik eignen, weber sis in Form ihrer nichttoxischen Salze, ebensogut aber auch ale frein Säuren oder als Ester der Säuren mit einfachen aliphatiachen Alkoholen verwendet werden können. Die neuen Verbindungen weisen ein e breite Einsatzfähigkeit und können in Form von Losungen, Emulsionen oder feinsten Suspensionen, beispielsweise In Wasser oder auch in C'len, zur Anwendung gelangen. Als bevorsugte Anwendungagabieto für wlsserige Lösungen sind die intravenöse Cholangiographie und Cholacystographie zu nennen.It was found that the new compounds according to formula I excellent due to its very low toxicity and gluten tolerance suitable for use in X-ray diagnostics, weber sis in the form of their non-toxic Salts, but also all free acids or as esters of acids with simple ones aliphatic alcohols can be used. The new connections instruct e broad applicability and can be in the form of solutions, emulsions or the finest Suspensions, for example in water or in C'len, are used. The preventive use of aqueous solutions is intravenous cholangiography and cholacystography.
Die Herstellung der Wirkstoffe der erfindungsgemäßen Röntgenkontrastmittel der Formel I gelingt durch Onaetzunc der nouen TI-substitu ierten Carbaminoyl-2,4,6-trijodbenzoylchloride der allgemeinen Forml I I I in der R1 und R2 wie oben definiert sind, mit Aminosäuren der allgemeinen Formel III : tt der R3 und X wie obon dofiaiert aind, oder mit deren Betern bei erhöhter Temperatur, worauf anschließend vorhandene Ester-Suppen gewünschtenfalls verseift und die entstandenen Säuren in Salze übergeführt oder die Säuren aus Salzen in Freiheit gesetzt werden.The active ingredients of the X-ray contrast media of the formula I according to the invention are prepared by adding the new TI-substituted carbaminoyl-2,4,6-triiodobenzoyl chlorides of the general formula III in which R1 and R2 are as defined above, with amino acids of the general formula III: tt the R3 and X are dofiaiert as obon, or with their prayers at elevated temperature, whereupon the existing ester soups, if desired, are saponified and the acids formed are converted into salts or the acids are set free from salts.
Die Reaktion wird bevorzugi, in einem inerten organischon Flüaaig keitsmedium durchgeführt, wobei beispielsweise Chloroform, Ac@ton, Dioxan, Tetrahydrofuran, Methyläthylketon, Chlorbenzol, Toluol usw. genannt werden können. Anstelle von organischen Lösungsmitteln kann auch in Wasser oder einer Mischung von Wasser mit aines erganischen Lösungsmittel, das mit Wasser mischbar ist, gearbeitet wurden. Es ist aber auch die Durchführung ohne Lösungsmittel möglich.The reaction is preferably carried out in an inert organic liquid keitsmedium carried out, for example chloroform, Ac @ ton, dioxane, tetrahydrofuran, Methyl ethyl ketone, chlorobenzene, toluene, etc. can be mentioned. Instead of organic Solvents can also be in water or a mixture of water with aine organic Solvent, which is miscible with water, were worked. It is also it can be carried out without a solvent.
Die lerung der Verbindungen der Formel I gelingt durch Eindampfen der vorher durch verachledene Waschprozesse gereinigten Mauag, worauf der ale Bindampfrückatand anfallende Eeter meißt @ofort verseift wird. Die Isolierung von Säuren und Salzen aus der Ver@eifungslösung kann auf übliche Weise erfolgen.The compounds of the formula I can be obtained by evaporation the Mauag, previously cleaned by neglected washing processes, whereupon the all binding steam residue accruing Eeter meißt @ immediately saponified. Isolation from acids and salts from the saponification solution can be done in the usual way.
Die Herstellung der Säurechloride der Formel II gelingt durch Oaeetaung der entsprechenden Carbonaauren mit Thionylchlcrid.The acid chlorides of the formula II are prepared by oxygenation of the corresponding carbonic acids with thionyl chloride.
Die Carbonsäuren werden durch Desaminierung der Trijod-aminoisophthalsäurehalbamide der Formel IV: erhalten.The carboxylic acids are obtained by deamination of the triiodo-aminoisophthalic acid half-amides of the formula IV: obtain.
Die bevors Anwendungsform der erfindungsgemäßen Verbindungen sind Salze, die in Wasser gelöst als Injektionslösungen oder a sur intravenösen Choleoystographie der Cholangiographie verabreicht werden können. Als solche Salze können beispielsweise die Natrium-, die Metbylglucamin-und die Diäthanolaminsalze genannt werden.The prior use form of the compounds according to the invention are Salts dissolved in water as solutions for injection or a sur intravenous choleoystography can be administered to cholangiography. As such salts, for example the sodium, methylglucamine and diethanolamine salts are mentioned.
Die Verbindungen der allgemeinen Formel I existieren zum Teil in swei geometrisch isomeren @ormen, deren Auftrennung prinzipiell möglich test.Some of the compounds of the general formula I exist in swei geometric isomeric forms, the separation of which is possible in principle test.
Anhand folgender Beispiele wird das Verfahren zur Herstellung der « Röntgenkontrastmittel im einzelnen beschrieben: Beispiel 1: 40,25 g 3-(N-Methylcarbaminoyl)-2,4,6-trijod-benzoylchlorid (0,07 Mole) werden in 70 ml Chloroform auspendiert und 22,35 g ß-n-Propylaminopropionsäuremethylester (0,154 Mole) eingetragen. Das Reaktionsgut wird 1, 5 Stundsn as bris bei aufgesetzten Rückflußkühler unter Rühren erhitzt. Nach Erkalten wird mit Chloroform verdünnt und mit verdünnter RCl, Wasser, Natriumbicarbonat-Lösung und Wasser gründlich ausgeschüttelt.The following examples illustrate the process for producing the «X-ray contrast media described in detail: Example 1: 40.25 g of 3- (N-methylcarbaminoyl) -2,4,6-triiodo-benzoyl chloride (0.07 moles) are suspended in 70 ml of chloroform and 22.35 g of methyl β-n-propylaminopropionate (0.154 moles). The reaction material is 1, 5 hours sniff as bris when attached The reflux condenser is heated with stirring. After cooling, it is diluted with chloroform and shaken thoroughly with dilute RCl, water, sodium bicarbonate solution and water.
Die mit Calciumchlorid getrocknete und über Baliumearbonat filtrierte Chloroformlösung wird zur Trockene verdampft. Der ölige reste 35 g, in 35 ml Méthanol gelöst, scheidet nach Zugabe von Xther 16, 25 g kristallisierten N- (3-N'-Mothylcarbaminoyl--2,4,6-trijodbenzoyl)-N-n-propyl-ß-aminopropionsäuremethylester vom Fp. 142 - 149°C ab. 15¢74 g dieses Esters ergeben bel der Vereeifung durch Kochen nit 26 ml t n NaOH und anschließendem Ansäuern mit Salsodure 13,6 g farblose N-(3-N'-Methylcarbaminoyl--2,4,6-trijod-benzoyl)-N-n-propyl-ß-aminopropionsäure vom 7p. 262-2650.The dried with calcium chloride and filtered through balium carbonate Chloroform solution is evaporated to dryness. The oily residue 35 g, in 35 ml of methanol dissolved, after addition of Xther 16, 25 g of crystallized N- (3-N'-Mothylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-propyl-ß-aminopropionate separates from m.p. 142-149 ° C. 15 ¢ 74 g of this ester yield bel Frosting by boiling with 26 ml of t n NaOH and subsequent acidification with Salsodure 13.6 g colorless N- (3-N'-methylcarbaminoyl-2,4,6-triiodo-benzoyl) -N-n-propyl-ß-aminopropionic acid from 7p. 262-2650.
Der Eindampfrest der Estermutterlauge stellt 40,9 g eines öligen Ester@ dar, der bei der Veroeifang mit 70 ml 1 n NaOH und 40 ml Methanol eine Rohsäure liefert, die aus Methanol kristallisiert.The evaporation residue of the ester mother liquor represents 40.9 g of an oily ester @ represents, the Veroeifang with 70 ml of 1N NaOH and 40 ml of methanol a crude acid supplies, which crystallizes from methanol.
Man erhält so noch weitere 11,5 g einer Säure vom Fp. 262 - 264°C.A further 11.5 g of an acid with a melting point of 262 ° -264 ° C. are obtained in this way.
Aus der Matterlauge scheidez sikh auf Zugabe von 90 ml H2O 9,6 g Säure aus, so daß inegesamt 34,7 g N-(3-N'-Methylcarbaminoyl--2,4,6-trijodbenzoyl)-N-n-propyl-ß-aminopropionsäure erhalten pardon.Separate from the Matterlauge on the addition of 90 ml H2O 9.6 g acid so that a total of 34.7 g of N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-propyl-ß-aminopropionic acid get pardon.
Aut analoge Weise können folgende Verbindungen hergestellt werden: N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-ß-aminopropionsäure Fp. 265-268°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-methyl-ß-aminopropionaaure Fp. 260-268C N- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-äthyl-ß-aminopropionaaure Fp. 262-2660 N- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-isopropyl-ß--aminopropionsäure Fp. 280 - 283°C N- -(3-N'-Methylcarbaminoyl-2,4, 6-trijodbenaoyl)-N-allyl-B-aminopropionsäure Fp. 219 - 223°C If- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-phenyl-ß-aminopropioSure Pp. 222-227 (' N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-2'-hydroxyäthyl--ß-aminopropionsäure Fp. 188 - 193°C N- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-3'-methoxypropyl --ß-aminopropionsäure Fp. 109 - 121°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-@-@-f@@@@@@@@@yl--0-aainopropionsE Fp. 217 - 221°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-amino@ssigsäure 1^p. 26-263C N- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-methyl-aminoeaaigeaure Fp. 17J-175°C N- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-n-butylaminoessigsäure Fp. 247-2519C N-(3-N'-Methylcarbaminoyl-2, 4, 6-trijodbensoyl)-N-allyl-aminoessigsäure Pp. 162-167 oc N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-n-propyl-ß--amino-α-methylpropionsäure Fp. 185 - 191°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-allyl-ß-amino--α-methylpropionsäure Pp. 130 - 136°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-3'-methoxypropyl--ß-amino-α-methylpropionsäure amorph, Methyleater Fp. 145 li- (3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-allyl-ß-aminobutSorokure Pp. 130 - 141°C N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)-N-3'-methoxypropyl-ß-aminobuttersäure, amorph.The following connections can be established in an analogous manner: N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -β-aminopropionic acid m.p. 265-268 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-methyl-ß-aminopropionic acid m.p. 260-268C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-ethyl-β-aminopropionic acid M.p. 262-2660 N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-isopropyl-β-aminopropionic acid Mp 280-283 ° C N- - (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-B-aminopropionic acid Mp. 219-223 ° C. If- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-phenyl-β-aminopropioic acid Pp. 222-227 (' N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-2'-hydroxyethyl-β-aminopropionic acid Mp 188-193 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-3'-methoxypropyl --β-aminopropionic acid m.p. 109 - 121 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) - @ - @ - f @@@@@@@@@@ yl - 0- aainopropionsE M.p. 217-221 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -amino-acetic acid 1 ^ p. 26-263C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-methyl-amino acid acid Mp.17-175 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-butylaminoacetic acid M.p. 247-2519C N- (3-N'-methylcarbaminoyl-2,4,6-triiodo-likeyl) -N-allyl-aminoacetic acid 162-167 oc N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-propyl-β-amino-α-methylpropionic acid Mp 185-191 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-β-amino-α-methylpropionic acid Mp 130-136 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-3'-methoxypropyl-β-amino-α-methylpropionic acid amorphous, methyl ester, m.p. 145 li- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-β-aminobut-butorokure Pp. 130 - 141 ° C N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-3'-methoxypropyl-ß-aminobutyric acid, amorphous.
In analoger Weise nur unter Verwendung von 3-N-Dimethylcarbaminoyl-2,4,6-trijodbemzoylchlorid als Säurechlorid werden erhslteas N-(3-N'-Dimethylcarbaminoyl-2,4,6-trijodbenzoyl)-amino-essigsäure Pp. 158-169°C, amorph N- (3-N'-Dimethylcarbaminoyl-2,4,6-trijodbenzoyl)-N-allyl-ß-aninopropionsäure Fp. 104 - 114°C, amorph X (3-N'-Dimethylcarbaminoyl-2,4,6-trijodbenzoyl)-N-3'-methoxypropyl-ß-aminopropionsäure Fp. 87 - 99°C, amorph.In an analogous manner only using 3-N-dimethylcarbaminoyl-2,4,6-triiodobemzoyl chloride The acid chloride obtained is N- (3-N'-dimethylcarbaminoyl-2,4,6-triiodobenzoyl) -amino-acetic acid M.p. 158-169 ° C, amorphous N- (3-N'-dimethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-β-aninopropionic acid M.p. 104-114 ° C., amorphous X (3-N'-dimethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-3'-methoxypropyl-β-aminopropionic acid M.p. 87-99 ° C, amorphous.
Derivate der 3-N-Äthylcarbaminoyl-2,4,6-trijodbenzoesäure werden erhalten, wenn in analoger Versuchsanordnung 3-N-Äthylcarbaminoyl--2,4,6-trijodbenzoyl-chlorid umgesetzt wird: N-(3-N'-Äthylcarbaminoyl-2,4,6-trijodbenzoyl)-N-allyl-aminoessigsäure Fp. 130 - 145°C, amorph N-(3-N'-Äthylcarbaminoyl-2,4,6-trijodbenzoyl)-ß-aminopropionsäure n. 286 - 289°C N-(3-N'-Äthylcarbaminoyl-2,4,6-trijodbenzoyl)-N-äthyl-ß-aminopropionsäure Fp. 237 - 240°C N-(3-N'-Äthylcarbaminoyl-2,4,6-trijodbenzoyl)-N-3-methoxypropyl--ß-amino-α-methylpropionsäure Fp. 107 - 114°C, amorph Ferner It8Sa analog don den-orliegenden Beiepielen arhaltan werden: N- (3-N'-3'-Methoxypropyl -carbaminoyl-2,4,6-trijodbenzoyl)-N--methyl-aminoessigsäure Fp. 199 - 202°C N- (3-N'-3'-Methoxypropyl-carbaminoyl-2,4,6-trijodbenzoyl)-N--isopropyl-ß-aminopropionsäure Fp. 118 - 129°C, amorph N- 3-N'-3'-Methoxypropyl -carbaminoyl-2,4,6-trijodbenzoyl)-N--phenyl-ß-aminopropionsäure Fp. 218 - 221°C N-(3-N'-ß-Hydroxyäthylcarbaminoyl-2,4,6-trijodbenzoyl)-2--furanomethyl-aminoessigsäure Fp. 215 - 219°C N- (3-N'-ß-Hydroxäthylcarbaminoyl-2,4,6-trijodbenzoyl)-N-n--propyl-ß-aminobuttersäure Fp. 134 - 143°C, amorph N-(3-N'-ß-Hydroxyäthylcarbaminoyl-2,4,6-trijodbenzoyl)-N-allyl-ß--awt&oproplcnwaarePp.H9-1300,amorphe In nachfolgenden werden Beispiele für die Herstellung der en RCntgenkontrMtmittel gegebene Beispiel 2t 684,07 g N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)--N-n-propyl-ß-amino-α-methylpropionsäure werden in 1000 ml 1 n IhOE gelöst, 17,1 g Polyvinylpyrrolidon darin in Lösung gebracht und auf 1710 ml aufgefüllt. Man erhält eine Lösung mit e Gehalt von 40,0 g Säure auf 100 ml Lösung, die für Injektionszwecke geeignet ist.Derivatives of 3-N-ethylcarbaminoyl-2,4,6-triiodobenzoic acid are obtained, if in an analogous experimental arrangement 3-N-Ethylcarbaminoyl - 2,4,6-triiodobenzoyl chloride is reacted: N- (3-N'-Ethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-aminoacetic acid Mp. 130-145 ° C, amorphous N- (3-N'-Ethylcarbaminoyl-2,4,6-triiodobenzoyl) -ß-aminopropionic acid n. 286-289 ° C N- (3-N'-Ethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-ethyl-β-aminopropionic acid Mp. 237-240 ° C N- (3-N'-Ethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-3-methoxypropyl-β-amino-α-methylpropionic acid Mp. 107-114 ° C., amorphous. It8Sa is also analogous to the present examples are: N- (3-N'-3'-methoxypropyl-carbaminoyl-2,4,6-triiodobenzoyl) -N-methyl-aminoacetic acid M.p. 199-202 ° C N- (3-N'-3'-methoxypropyl-carbaminoyl-2,4,6-triiodobenzoyl) -N-isopropyl-β-aminopropionic acid M.p. 118-129 ° C, amorphous N-3-N'-3'-methoxypropyl-carbaminoyl-2,4,6-triiodobenzoyl) -N-phenyl-β-aminopropionic acid Mp. 218-221 ° C. N- (3-N'-β-hydroxyethylcarbaminoyl-2,4,6-triiodobenzoyl) -2-furanomethylaminoacetic acid Mp. 215-219 ° C N- (3-N'-ß-Hydroxäthylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-propyl-ß-aminobutyric acid M.p. 134-143 ° C., amorphous N- (3-N'-β-hydroxyethylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-β-awt & oproplcnwaarePp.H9-1300, amorphous The following are examples of the production of the X-ray control agents Example given 2t 684.07 g of N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-n-propyl-β-amino-α-methylpropionic acid are dissolved in 1000 ml of 1N IhOE, and 17.1 g of polyvinylpyrrolidone are dissolved therein and made up to 1710 ml. A solution containing 40.0 g of acid is obtained to 100 ml of solution suitable for injections.
Beispiel 3 ! 654, 0 g N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)--N-allyl-aminoessigsäure werden in 2000 ml 0,5 n NaOH gelöst und ein Gesamtvolumen 2616 ml aufgefüllt. Die erhaltene Lösung hat einen Gehalt von 25,0 g Säure pro 100 ml Lösung.Example 3! 654.0 g of N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-allyl-aminoacetic acid are dissolved in 2000 ml of 0.5N NaOH and a total volume of 2616 ml is made up. the The solution obtained has a content of 25.0 g of acid per 100 ml of solution.
Baiapiel4<714,10gN-(3-N'-Methylearbamincyl-2,4,6-trijodtwNma9)-@-meth -4jtMthcatyp<ropyl-a-amino-aetlproooaamrewerdemmit193,20< N-Methyl-D-glucosamin zunächst in wenig Wasser gelöst, dann auf 1785 ml Gesamtvolumen aufgefüllt. Die Lösung enthält dann 40,0 g Säure auf 100 ml Lösung und ist für Injektions@wecke geeignet.Baiapiel4 <714.10gN- (3-N'-methylearbamine-yl-2,4,6-triiodtwNma9) - @ - meth -4jtMthcatyp <ropyl-a-amino-aetlproooaamrewerdem with 193.20 <N-methyl-D-glucosamine first dissolved in a little water, then made up to a total volume of 1785 ml. the The solution then contains 40.0 g of acid per 100 ml of solution and is for injection purposes suitable.
Beispiel 5: 730,04 g N-(3-N'-Methylcarbaminoyl-2,4,6-trijodbenzoyl)--N-2-furanomethyl-ß-aminopropionsaures Natrium werden unter gjelindem Erwärmen in Wasser klar gelöst und auf ein Endvolumen von 2832 al aufgefallt. Die Lösux4 hat sine Konzentration van 25,0 g Säure auf 100 ml Lösung und ist für Injektionszwecke geei@net. Example 5: 730.04 g of N- (3-N'-methylcarbaminoyl-2,4,6-triiodobenzoyl) -N-2-furanomethyl-β-aminopropionic acid Sodium is dissolved to give a final volume in water with slight warming of 2832 al. The Lösux4 has a concentration of 25.0 g of acid per 100 ml of solution and is suitable for injections.
Auoh die übrigen, nach Beiapiel t hergestellten Verbindungen aS auf analoge Weise in Lösungen übergeführt werden. fttentansprdahesAlso the other connections aS made according to Example t can be converted into solutions in an analogous manner. fttentansprdahes
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4269819A (en) * | 1978-07-14 | 1981-05-26 | Schering Aktiengesellschaft | 2,4,6-Triiodobenzonitrile derivatives and X-ray contrast media comprising them |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4269819A (en) * | 1978-07-14 | 1981-05-26 | Schering Aktiengesellschaft | 2,4,6-Triiodobenzonitrile derivatives and X-ray contrast media comprising them |
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